MARGARET HEMMER Department of Anesthesiology and Polyvalent Intensive Care Centre Hospitalier de Luxembourg Luxembourg, Luxembourg

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1 POST SURGICAL MENINGITIS EUROANESTHESIA 2005 Vienna, Austria May RC3 MARGARET HEMMER Department of Anesthesiology and Polyvalent Intensive Care Centre Hospitalier de Luxembourg Luxembourg, Luxembourg Saturday May 28, :00-14:45 Room E2 PATHOGENESIS Nosocomial infections after elective or emergency neurosurgical procedures are associated with increased mortality and worsening of neurological outcome. Cerebrospinal fluid (CSF) has limited resistance against infection due to its low level of immunoglobulins and complement and a septic perioperative inoculation results in rapid microbial proliferation and life-threatening infection. Nosocomial ventriculitis is related to the use of external catheters for measurement of ventricular pressure and CSF drainage and to the siting of implanted ventricular drainage shunts. Retrograde colonisation and infection, similar to that occurring with intravascular devices, is responsible for development of intraventricular catheter related ventriculitis. Wound infection, shunt obstruction and presence of a foreign body covered with bacterial biofilm within intracranial contents are responsible for development of ventriculitis after shunting procedures. Nosocomial meningitis following neurosurgical procedures may be due to airborne or skin micro organisms but is more frequently related to the use of foreign materials, grafts or prosthetic devices. It may also occur after a mechanical breach of the central nervous system (CNS) during neurosurgical procedures with concomitant contamination of the CSF by the bacterial flora of the paranasal sinuses or nasal mucosa. Hematogenous spread rarely causes postoperative meningitis. Post-traumatic meningitis (with or without surgery) may occur in patients with basal skull fractures, with severe maxillofacial injury and in patients with traumatic pneumoencephalus. The pathogenesis of posttraumatic meningitis is related to the presence of a dural fistula and CSF leak followed by contamination and infection of CSF by the bacterial flora of nasopharynx or external auditory canal. Patients with penetrating brain injury are also at risk of intracranial infection because of the projection of contaminated foreign objects (skin, hair, bone fragments) into the intracranial contents. Paranasal sinus damage and CSF leaks are also common in this category of patients. NOSOCOMIAL VENTRICULITIS Nosocomial ventriculitis occurs in 0-22 % (commonly about 10%) of patients with a ventricular catheter and in 2-27% of patients with a CSF shunt. Early recognition of ventricular infection is essential to prevent the development of overwhelming meningitis. The frequency of infection depends on the technique of intraventricular device insertion and on later clinical management [1,2]. Definition of nosocomial ventriculitis differs in different studies but always includes a culture of a recognized pathogen from the ventricular CSF along with clinical signs of infection (fever or hypothermia, neurological deterioration). However, if common skin flora such as coagulase negative staphylococcus, corynebacterium, bacillus, micrococcus or propionibacterium spp. are isolated one or more supplementary criteria must be present: a Gram stain of the original CSF sample that produce a finding consistent with the organism cultured, a decrease in CSF glucose level, an increase in the CSF lactate and protein level or a finding of neutrophil pleocytosis [2]. Increase in serum procalcitonin and C-reactive protein levels and MR or CT imaging showing contrast enhancement of ventricular ependymal tissue can also contribute to the diagnosis. Early detection of ventriculitis is very difficult in patients with intraventricular haemorrhage in whom the CSF is heavily contaminated by blood. A group of Austrian investigators has recently proposed a new diagnostic parameter called cell index which represents the relationship of the leucocyte and erythrocyte count in CSF and peripheral blood, expressed as an absolute value. They assumed that the increase in cell index was predictive of ventriculitis and demonstrated in a small pilot study of 13 patients that diagnosis of ventriculitis based on cell index values was achieved 72 hours before conventional methods [3]. This interesting concept needs to be verified in a much larger number of patients. 101

2 Colonisation of ventricular catheters is defined as the presence of skin bacteria in multiple cultures or on Gram stain without clinical or biological signs of infection. An isolated positive CSF culture and/or Gram stain without clinical or biological signs of infection is considered to be contamination [1]. Gram-positive infections related to the use of transcutaneous catheters have been predominant: Coagulase negative staphylococci, S. Aureus and diphteroids. More recently, an increase of Gram-negative, often multiresistant micro organisms (K. pneumoniae, K. oxytoca, Enterobacter cloacae, Serratia marcescens, Proteus mirabilis, and Acinetobacter anitratus) has been reported as well as nosocomial infections caused by MRSA and by Candida sp. Preventive strategies may prevent infection. Placement of intraventricular catheters should be performed under sterile conditions, preferably in the operating theatre and the catheter should be tunnelled in a retrograde fashion to the skin exit site and connected via a 3 way stopcock to an external pressure transducer and CSF closed drainage system. The catheter should be sutured in place and a non occlusive dressing applied. Antibiotic prophylaxis (three doses or less) with oxacillin or a first generation cephalosporin is usually recommended. The wound dressing should be changed only if soiled or loose. The system should remain entirely closed and samples of CSF should be obtained only if the clinical condition requires further evaluation (fever, neurological deterioration). Routine catheter exchange after 5 days has been recommended by several experts but more recent studies have shown that removal and exchange should be done only when the catheter becomes obstructed or infected. Whenever possible a fibreoptic non ventricular device for measurement of intracranial pressure (subdural or intraparenchymal) should be used. Several risk factors for ventriculostomy related infection has been evaluated: host related factors, neurosurgical diagnosis, type of neurosurgical procedure, previous craniotomy, previous ventricular drainage, breaks in the integrity of the closed system, disconnections, irrigation of the system, dressing changes, presence of CSF leak at the site of infection and the duration of catheter insertion. Although most studies have shown that the risk of catheter infection increases with the drainage time a recent prospective Austrian study did not found a significant correlation. The only parameter that significantly correlated with positive CSF culture was the increase in CSF leucocyte count. In contrast, another prospective cohort study from Johns Hopkins Hospital in Baltimore revealed that CSF leakage at the insertion site and the duration of intraventricular catheterisation (average duration 5.07 days (range 1-23days) for the noninfected ; 8.45 days (range 2-23days) for the infected) were the only independent risk factors for ventriculostomy related infections. In this study a clear shift from Gram-positive towards Gram-negative organisms was noted and the authors concluded that the use of prophylactic antibiotics directed at Gram-positives during the period of ventricular drainage was the cause of microbiological change [2]. Another recent retrospective study investigated the role of prophylactic antibiotics given for the duration of external ventricular drainage and compared it with periprocedural prophylaxis only (IV cefuroxime 1.5g every eight hours, three or less doses). The overall rate of ventriculitis was 3.9%; the infection rates in both groups were similar and the authors concluded that prophylactic antibiotics did not significantly reduce the rate of ventriculitis in patient with external ventricular catheter but that they may contribute to selection of multiresistant organisms. Discontinuing the use of prophylactic antibiotics for the whole duration of external ventricular drain at the authors institution would save approximately 80,000 dollars per year in direct drug costs [5]. Mortality rates attributable to nosocomial ventriculitis are difficult to evaluate because of the severity of underlying neurological disease. However these infections significantly increase the length of the hospital stay and the overall cost of hospitalisation. VENTRICULAR SHUNT INFECTION Ventricular shunt infections may occur several weeks or months after shunt implantation and are usually associated with fever, headache, nausea, changes in mental status and abdominal pain. Bacteriemias occur frequently. Ménage symptoms are rare with ventriculoperitoneal or ventriculoventricular shunts. The rate of infection with lumboperitoneal shunts is lower than with ventriculoperitoneal shunts. Shunt obstruction, disconnection and malfunction frequently precede shunt infection [6]. 102

3 Microbiological diagnosis of shunt related ventriculitis is obtained by the puncture of shunt reservoir, culture of the scalp wound and the tissue around the shunt and by a lumbar puncture. The organisms most frequently isolated are S. epidermidis, S. aureus and diphteroids (65-80%) but Gram negative, often multiresistant, bacteria are found in 20% of shunt infections. Isolated cases of methicillin resistant staphylococcus aureus (MRSA) and vancomycin resistant enterococcus (VRE) were recently reported. Fungal infection of ventricular shunts (predominantly due to Candida sp.) are increasing, in particular in patients who previously received systemic antimicrobial agents or corticosteroids, were colonized with Candida sp. or developed a concomitant bacterial and fungal ventriculitis [7,8]. Treatment of shunt infections includes parenteral antibiotics and shunt removal with insertion, if necessary, of temporary external ventricular drainage. All parts of the removed shunt should be cultured. MENINGITIS AFTER CLEAN AND CLEAN-CONTAMINATED NEUROLOGICAL PROCEDURES Incidence of meningitis in clean and clean-contaminated no-shunt neurosurgical procedures is very low and varies between 0.8% to 2% in recent studies. The US National Nosocomial Infection Surveillance System (NNISS) risk score was recently validated for the neurosurgical population in a prospective multicenter trial of 2944 neurosurgical patients in France. This score predicts the risk of acquiring surgical site infections and includes three risk factors: ASA preoperative score of 3, 4 or 5, an operation classified as contaminated or dirtyinfected and operation lasting over 4 hours. The authors have demonstrated that the index was generally predictive in patients with score 0 (indicating lowest infection rate) and that there was a well correlated progression in the risk of infection with higher scores. However, the NNISS score does not take into consideration specific post-and peri-operative problems which may influence the occurrence of deep wound infection (meningitis and abscess). The authors have performed a multivariate analysis which has shown that only the factors related with surgical technique (presence of peri-or post-operative CSF leak and early subsequent operation (usually for bleeding complications)) were independent predictors of meningitis and cerebral abscess. They have also found that the use of antibiotic prophylaxis, although beneficial for incisional infections, had no influence on deep infection rates [9]. These conclusions were confirmed by other authors who also reported high rates of meningitis after elective neurosurgical procedures complicated by CSF leak [10]. Bacteriology of meningitis complicating clean and clean-contaminated neurosurgical procedures varies within different studies and depends on patients colonization and local microbial resistances. Recently French investigators from a single institution reported 2.3 % postoperative meningitis after craniectomies and 0.6 % after spinal surgery with 56 % Gram-positive bacteria (mostly MSSA and Coagulase-negative staphylococci ) and 44 % Gram-negative bacteria (mostly Enterobacteriaceae with few Pseudomonas and Corynebacterium sp) [11]. In other studies a higher proportion (60 70 %) of Gram-negative bacteria was reported. Pooled mortality rates in patients with postsurgical meningitis are 6 8 % but much higher rates were reported from single institutions for Candida meningitis (27 %), MRSA meningitis (50 %) and Gram-negative meningitis (58 %). However these results included patients with shunt surgery, ventriculostomies and surgery for trauma. ASEPTIC MENINGITIS AFTER NEUROSURGICAL PROCEDURES Clinical symptoms and biological inflammatory findings in CSF similar to bacterial meningitis but with negative cultures are frequently observed. Aseptic meningitis is thought to be the result of chemical irritation caused by blood degradation products released into the subarachnoid space during surgery or by factors released by dural substitutes. Definite diagnosis of aseptic meningitis requires extremely cautious clinical observation and repetitive CSF leucocytes, glucose, protein and lactate measurements and serial bacterial cultures [12]. A prospective French study demonstrated bacterial involvement in three cases of aseptic meningitis [13]. The British Society for Antimicrobial Chemotherapy recommends empirical antibiotic treatment in all patients who present with clinical signs of post-neurosurgical meningitis. This treatment may be discontinued after 2 or 3 days if the Gram-stains and cultures of CSF remain negative thereby confirming the diagnosis of aseptic meningitis [12]. 103

4 ANTIBIOTIC PROPHYLAXIS FOR CLEAN NEUROSURGICAL PROCEDURES Antibiotic prophylaxis is indicated for those procedures with high infection rates, those involving implantation of prosthetic material and those in which the consequences of infection are serious. Compared to other surgical specialities neurosurgery carries a low risk of infection but the consequences of postoperative meningitis or ventriculitis can be devastating. Several randomized control studies have proven the efficacy of prophylactic antibiotics in clean brain and spine surgery [14, 15]. In spite of these findings the issue of antibiotic prophylaxis for clean neurosurgical procedures remains controversial [16]. Antibiotic prophylaxis is costly, may produce serious drug reactions, promotes the development of microbial resistance and may cause super infection. A recent meta-analysis of 2001 patients from 6 randomised control trials has shown that the decrease in infection rates was significant (from 7.24 % in controls to % in group with prophylaxis) but the majority of protocols of prophylaxis used broad spectrum antibiotics or antibiotic combinations likely to produce resistance [16]. For clean neurosurgical procedures ceftazoline or oxacillin (with clindamycin as an alternative for beta-lactam allergy) offer sufficient prophylaxis and amoxicillin clavulanate may be administered for clean contaminated or emergency surgery [11]. POST-TRAUMATIC MENINGITIS The incidence of post-traumatic meningitis varies from 0.2 to 17.8 %. Head injury patients frequently present with basal skull fractures and CSF leaks (otorrhoea or rhinorrhoea). They often require emergency operations (evacuation of traumatic haematoma, decompressive craniectomy, ventricular drainage) and delayed surgical interventions for repair of CSF leak or replacement of scalp bones. They may also have delayed appearance of previously unrecognized CSF fistulae which may cause of meningitis 2 to 25 years after the injury. Bacteriological findings in early post traumatic meningitis are related to the flora of nasal cavity and external auditory canal (Pneumococcus, Haemophilus influenzae, S. aureus, E. coli). If the interval between the injury and infection is prolonged and if the patient received broad spectrum antibiotics for other trauma related infections, Gram negative multiresistant micro organisms are found in CSF cultures ( E. coli, Enterobacter sp, K. pneumoniae, Acinetobacter sp, Proteus sp). Several studies have investigated the use of prolonged prophylaxis with various antibiotic regimens for the whole period of CSF leak with contradictory results. A meta-analysis of 1241 patients with basal fractures and CSF leak (including children) from 12 studies has shown that antibiotic prophylaxis during the period of CSF leak after basal skull fracture did not prevent meningitis [17]. Antibiotic prophylaxis is also widely used in penetrating brain injury but neither the optimum duration nor the optimum regimen have yet been determined. EMPIRIC AND DEFINITE ANTIBIOTIC THERAPY OF POSTSURGICAL MENINGITIS Although postsurgical meningitis is less virulent than community acquired meningitis, rapid empiric therapy based on knowledge of the usual causative agents and local microbial sensitivities is recommended. The Working Party of the British Society for Antimicrobial Chemotherapy proposed the following protocol, based on the collective experience of the members and on published evidence [12]. A third generation cephalosporin (cefotaxime or ceftriaxone) should be given as first line therapy. Ceftazidime should be reserved for patients who recently received broad spectrum antibiotics or who have a confirmed Pseudomonas meningitis. Suspected or confirmed ESBL-producing Enterobacteriaceae and Acinetobacter sp should be treated by meropenem. MSSA meningitis should be treated with flucloxacillin and patients with MRSA meningitis should receive vancomycin or teicoplanin together with rifampicin. As glycopeptides penetrate poorly into the CNS the trough and peak concentrations must be monitored daily. Administration of intrathecal vancomycin may be necessary in patients who do not respond to systemic therapy. Serial CSF cultures every 4 5 days should be performed to follow bacterial resistance patterns. Treatment for two weeks is sufficient for S. Aureus, but Gram negative meningitis should be treated for at least three weeks and if the pathogen is not eradicated by systemic therapy alone, intrathecal administration with gentamicin should be considered. 104

5 For ventriculitis in patients with external ventricular drains where coagulase negative staphylococci are predominant, the Working Party proposes intraventricular instillation of vancomycin 5 to 20 mg depending on ventricular volume and then clamping the drain for approximately 15 minutes. The interval between consecutive administrations of vancomycin should depend on the volume of CSF drainage. The safety and efficacy of intrathecal vancomycin was recently tested in a prospective randomized trial [18]. Another protocol based on a prospective study of 6447 consecutive patients was proposed by neurosurgeons and neuroanesthesists from Pitié Salpétrière Hospital in Paris. In their series the incidence of staphylococci (especially coagulase negative staphylococci and MRSA) was higher in patients with CNS shunting devices whereas Enterobacteriaceae were more common in patients with no shunt. They propose the administration of Cefotaxime alone in patients with no CSF shunt and Cefotaxime with high dose vancomycin in post neurosurgical patients with meningitis who have a ventriculostomy or CSF shunt [11]. Recently several case reports of successful treatment of post surgical meningitis and ventriculitis due to Coagulase negative staphylococci and VRE with linezolid were published [19]. High concentrations of linezolid were documented in CSF. Linezolid may provide a valuable option for treatment of Gram positive meningitis when the use of vancomycin is contraindicated. REFERENCES 1. Lozier AP, Sciacca RR, Romagnoli MF, Sander Conolly E. Ventriculostomy related infections: A critical review of the literature. Neurosurgery 2002 ; 51 : Lyke KE, Obasanjo OO, Williams MA, O Brien M, Chotani R, Perl TM. Ventriculitis complicating Use of Intraventricular Catheters in Adult Neurosurgical Patients. Clin Infect Dis 2001 ; 33 : Pfausler B, Beer R, Engelhardt K, Kemmler G, Mohseripour I, Schmutzhard E. Cell index a new parameter for the early diagnosis of ventriculostomy (external ventricular drainage) related ventriculitis in patients with ventricular hemorrage. Acta Neurochir (WIEN) 2004 ; 146 : Pfisterer W, Mühlbauer M, Czech T, Reinprecht A. Early diagnosis of external ventricular drainage infection: results of a prospective study. J Neurol Neurosurg Psychiatry 2003 ; 74 : Alleyne CH J, Hassan M, Zabramski JM. The efficacy and cost of prophylactic and periprocedural antibiotics in patients with external ventricular drains. Neurosurgery 2000; 47 : Vanaclocha V, Saiz Sapena N, Leiva J. Shunt malfunction in relation to shunt infection. Acta Neurochir (Wien) 1996 ; 138 : Kang JK, Lee IW. Long term follow up of shunting therapy. Childs Nerv Syst 1999 ; 15 : Geers TA, Gordon SM. Clinical significance of Candida species isolated from cerebrospinal fluid following neurosurgery. Clin Infect Dis 1999 ; 28 : Korinek AM. The French Study Group of Neurosurgical Infections.The SEHP and the C-CLIN Paris-Nord. Risk factors for neurosurgical site infections after craniotomy: a prospective multicenter study of 2944 patients. Neurosurgery 1997 ; 41 : Haile Mariam T, Laws E, Tuazon CU. Gram-Negative Meningitis associated with Transsphenoidal Surgery: Case reports and Review. Clin Infect Dis 1994 ; 18 : De Bels D, Korinek AM, Bismuth R, Trystram D, Coriat P, Puybasset L. Empirical treatment of Adult Postsurgical Nosocomial Meningitis. Acta Neurochir (Wien) 2002 ; 144 : Anonymous Infection in Neurosurgery Working Party of the British Society for Antimicrobial Chemotherapy. The management of neurosurgical patients with postoperative bacterial or aseptic meningitis or external ventricular drain associated ventriculitis. Br J Neurosurg 2000 ; 14 : Druel B, Vandenesch F, Greenland T, Verneau V, Gando J, Salord F, Christen R, Etienne J. Aseptic meningitis after neurosurgery : a demonstration of bacterial involvement. Clin Microbiol Infect 1996 ; 4 : Yu CT, Codamos LJ, Coronel RF. Antibiotic Prophylaxis in non-shunt, clean cranial surgical procedures : a metaanalysis. Phil J Microbiol Infect Dis 2000 ; 29 : Baker FG. Efficacy of Prophylactic antibiotic therapy in spinal surgery: a metaanalysis. Neurosurgery 2002 ; 51 : Savitz SI, Rivlin MM, Savitz MH. The ethics of prophylactic antibiotics for neurosurgical procedures. J Med Ethics 2002 ; 28 : Villalobos T, Arango C, Kubilis P, Rathore M. Antibiotic prophylaxis after basilar skull fractures: a metaanalysis. Clin Infect Dis 1998 ; 27 : Pfausler B, Spiss H, Beer R, Kampl A, Engelhardt K, Schober M, Schmutzhard E. Treatment of staphylococcal ventriculitis associated with external cerebrospinal fluid drains: a prospective randomized trial of intravenous compared with intraventricular vancomycin therapy. J Neurosurg 2003 ; 98 : Treatment of Meningitis due to Methicilin Resistant Staphylococcus epidermidis with Linozelid. Krueger WA, Kottler B, Will BE, Heiniger A, Guggenberg H, Unertl KE. J Clin Microbiol 2004 ; 42 :