Antibiotics and the Development of Resistance
Since their introduction into medical practice, antibiotics have played an enormous role in decreasing morbidity from bacterial infection and have therefore been invaluable in neurosurgical practice. Entities such as meningitis and brain abscess, which were associated with high mortality rates before antibiotic therapy, are now frequently cured with appropriate combinations of surgery and antibiotic therapy. Because of the immune-privileged nature of the central nervous system (CNS), the common use of implanted devices, and the frequent use of steroids, infection is of great concern in neurosurgical practice; therefore, the rational, effective use of antibiotics is of great importance. An understanding of antibiotic mechanisms of action and the mechanisms with which microbes develop resistance is essential for the neurosurgeon.
The intelligent use of antibiotics is crucial for the successful prevention and management of infections. The principle of using the agent with the narrowest spectrum for the least amount of time to eradicate a particular infection is well recognized, but not universally practiced. The lack of a definitive culture is often an impediment to successful treatment. Additionally, the incorrect assumption that antibiotics with broad coverage are more effective than an appropriate narrow-spectrum antibiotic against a particular microbial species can lead to antibiotic misuse. Vancomycin, for example, is no more effective against methicillin-sensitive Staphylococcus aureus than either cephazolin or oxacillin.
A second key principle for therapeutic success is that, although the excessive use of antibiotics should be avoided, complete eradication of an infection is necessary for a successful clinical outcome. Therefore, surgical treatment is necessary if hardware is involved (that may be removed), such as a cerebrospinal fluid (CSF) shunt or an intrathecal catheter. Similarly, if a suppurative collection exists, such as a bacterial brain abscess, subdural empyema, or cranial epidural abscess that is too large for antibiotic penetration, surgical evacuation is necessary. Attempting to treat an infection through medical management only, such as in the case of a partially drained abscess1 or an infected CSF shunt that is not removed,2 can often result in a recurrent infection.
In the practice of surgery, antibiotics have played an enormous role in preventing surgical site infections and in the provision of effective surgical treatment. Antibiotic prophylaxis, which is discussed in Chapter 14, is standard practice in neurosurgery. Postoperative infections, when they do occur, are treatable with antibiotics, although reoperation is often essential. Of course, antibiotic prophylaxis will not compensate for poor sterile technique, and in the case of contamination from a breach or from penetrating cerebral trauma, infections are likely to occur. Failure of wound healing due to lapses in surgical technique, poor nutritional status, or CSF fistula offers a portal for bacterial invasion that will occur despite antibiotic prophylaxis. In these circumstances, the identification of the infectious agent and its sensitivities is critical for the successful eradication of the infection, as is the removal of any modifiable risk factors for the development of infection.
In treating infections of the CNS, the concept of the blood–brain barrier (BBB) plays an important role. Antibiotic penetration into the central nervous system (CNS) is variable, which can influence antibiotic selection, although the BBB may be compromised during infection, allowing hydrophilic antibiotics to enter the CSF. Vancomycin and the fluoroquinolones, which are lipophilic molecules, cross the BBB particularly well. Aminoglycosides and β-lactam antibiotics are hydrophilic and therefore do not penetrate the BBB very easily. Intraventricular or intrathecal administration of antibiotics can provide direct entry into the CSF space; however, the presence of external ventricular drainage or a lumbar drain is required for drug instillation. Intraventricular antibiotics have been suggested both as treatment for ventriculitis3 and for prophylaxis at the time of surgery to prevent shunt infection.4 β-Lactam antibiotics can be epileptogenic and are therefore generally not administered via an intraventricular route despite their relatively poor penetration of the BBB.5
Allergies may also play a role in the choice of which antibiotic to use. Patients with chronic diseases may have had exposure to multiple antibiotics, with the opportunity to develop multiple sensitivities to the drugs. The specifics of a patient′s reaction to a particular allergy are important to note because some reactions may not be true allergies, and others, such as “red man syndrome” from vancomycin, may not preclude the use of the agent if it is given in concert with diphenhydramine.
Antibiotic resistance has been extensively discussed both in the scientific literature and the popular media, and its importance cannot be overstated. The rise in the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) has been well documented. In the United States from 1975 to 1991, the rate of MRSA infections in the hospital setting rose from 2.4 to 29%.6 Additionally, the incidence of community-associated MRSA infections has been on the rise.7 By the following decade, MRSA infections were estimated to account for approximately 2% of all hospital admissions.8 Vancomycin was developed with the intention that it would be highly resistant to the development of bacterial resistance, and its name is based on the fact that its developers thought that the resistant bacteria might be vanquished. Despite these high hopes, strains of vancomycin-resistant enterococci (VRE) and some strains of S. aureus that are vancomycin intermediate (VISA) or vancomycin resistant (VRSA) have been isolated. The newer drug linezolid is the first line in the treatment of infections resistant to vancomycin; however, the increased use of linezolid will no doubt ultimately lead to the development of strains resistant to this antibiotic.
Antibiotics are categorized into classes based on their structure and mechanisms of action. Antibiotics can further be classified as bacteriocidal or bacteriostatic. Bacteriostatic agents depend on the functional immune system to destroy the bacteria but may be as effective as bacteriocidal drugs in the right setting. The mechanisms and spectra of commonly used antibiotics are listed in Table 3.1 .
Antibiotic resistance occurs via multiple mechanisms (see Table 3.1 ). Resistance to β-lactam antibiotics occurs when bacteria express β-lactamase, an enzyme that simply breaks down the drug. Bacterial circumvention of the toxicity of several antibiotics occurs when the bacteria synthesize altered proteins that do not bind the drugs. This phenomenon occurs in resistance to aminoglycoside and macrolide antibiotics. A third mechanism of resistance involves the use of efflux pumps, such as in tetracycline resistance.
Genes for antibiotic resistance are often encoded on plasmids, which are extrachromosomal elements that replicate stably in bacterial hosts.9 Many plasmids are capable of conjugation, a process in which rapid transfer of the plasmid occurs between bacteria. Conjugation can occur across a wide array of species and can even occur from gram-negative to gram-positive bacteria and vice versa.
Because of the ease with which antibiotic resistance can spread from site to site within the body and between patients, the control of reservoirs of antibiotic resistance can be helpful in reducing hospital-acquired infections and those at the surgical site. Of utmost importance is rigorous adherence to protocols aimed at reducing the spread of antibiotic-resistant bacteria from patient to patient. Hand washing and gel-based decontamination, when practiced, reduce the prevalence of MRSA and other antibiotic-resistant bacterial strains within the hospital setting.10 Intranasal mupirocin administered preoperatively for decolonization of MRSA has been demonstrated in the orthopedic literature to reduce the rate of surgical site infections11 and may be useful in neurosurgical procedures. In settings with a high risk for MRSA infection, vancomycin is probably a better choice for preoperative prophylaxis than is cefazolin.12
The timing of antibiotic administration is another important consideration. In general, antibiotic administration should be delayed until a culture of the suspected site of infection has been obtained. The rate at which antibiotic administration decreases culture sensitivity is not known for most situations; however, unless the patient is critically ill and culture cannot be obtained in a timely fashion, it is reasonable in most situations to wait for the culture results. A frustrating situation arises when a known infection is being treated but positive cultures are not available from which to tailor antibiotic treatment. The length of treatment with antibiotics is also important because the premature cessation of treatment will often lead to the recurrence of infection and may place the patient at risk for antibiotic resistance. The timing of antibiotic administration in presurgical prophylaxis has been intensively scrutinized, and many institutions have protocols in place to maximize the effectiveness of presurgical antibiotics.
Antibiotic-impregnated materials have also been used in an attempt to prevent colonization and the subsequent infection of hardware. Shunt tubing impregnated with rifampin and clindamycin (Bactiseal; Codman, Raynham, Massachusetts) has been used with reports of success in lowering the rate of device-associated infection.13–16 Increased antibiotic resistance in isolates from infections that do occur have not been reported, but that possibility is at least a theoretical consideration. Data regarding similar antibiotic-impregnated external ventricular drains are less clear in revealing a therapeutic benefit.17 Antibiotic-coated sutures (Vicryl Plus; Ethicon, San Angelo, Texas) are also available, and they may decrease the rate of postoperative infection.18
Conclusion
The prevention and treatment of infections are an important part of neurosurgical practice. The optimal use of antibiotics is important in managing patients and in preventing the development and spread of antibiotic-resistant strains. Despite the availability of multiple classes of antimicrobial agents with diverse mechanisms of action, resistance will invariably develop with extensive antibiotic use and can spread rapidly within the hospital environment. Strict attention to hygiene, with pre- and postoperative protocols, can reduce surgical site infections. Appropriate treatment when infections do occur lowers the risk for recurrence and the spread of antibiotic-resistant pathogens.
Obviously, the neurosurgeon will not have the background of the microbiologist or pharmacologist when choosing an antibiotic regimen. For that reason, it is important for the neurosurgeon to work in concert with the infectious disease specialists and the pharmacist when necessary to devise treatment regimens for patients with infections of the CNS.
References
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