INTRODUCTION — Gram-negative bacilli are an important cause of nosocomial meningitis. Major risk factors for nosocomial meningitis include neurosurgery or head trauma within the past month, presence of a neurosurgical device, and a cerebrospinal fluid (CSF) leak. While Gram-negative bacilli remain an uncommon cause of community-acquired bacterial meningitis in adults, the frequency of cases arising from the community has increased substantially, from 3 percent of cases in older studies to over 75 percent of episodes in one newer study [1-4]. Acinetobacter baumannii is now the most common Gram-negative bacterium causing Gram-negative bacillary meningitis in the neurosurgical setting in parts of Europe, followed by Klebsiella pneumoniae [5,6].
Gram-negative bacillary meningitis is often fatal with reported mortality rates of 40 to 80 percent in adults and children, and complications are common in patients who survive [7,8]. As an example, the mortality rates among adults with both spontaneous and post-neurosurgical gram-negative bacillary meningitis in two studies were 53 and 57 percent [4,9]. These mortality rates were almost 20 times higher than the mortality rate of spontaneous bacterial meningitis due to Neisseria meningitides in adults, as reported in one of those same studies [4]. In another study conducted over a 21-year period, 61 percent of infants who survived gram-negative meningitis had developmental disabilities and neurologic sequelae [10].
The treatment of gram-negative bacillary meningitis will be reviewed here. The epidemiology, clinical manifestations, and diagnosis of this infection are discussed separately. (See "Gram-negative bacillary meningitis: Epidemiology, clinical features, and diagnosis".)
Additional discussion of the management of meningitis in children and adults is found elsewhere. (See "Bacterial meningitis in the neonate: Treatment and outcome" and "Bacterial meningitis in children older than one month: Treatment and prognosis" and "Initial therapy and prognosis of bacterial meningitis in adults" and "Treatment of bacterial meningitis caused by specific pathogens in adults".)
GENERAL PRINCIPLES FOR TREATMENT — The treatment of gram-negative bacillary meningitis is difficult. Despite appropriate therapy and an apparent clinical response, cerebrospinal fluid (CSF) cultures may remain positive for as long as 13 days after treatment is begun [11,12]. The average duration of therapy needed to sterilize the CSF is two to four days in adults and 2.8 to 8.2 days in neonates [11]. In a series of 98 neonates and infants, positive results were obtained on CSF cultures for one to 18 days after the commencement of antibiotic therapy (mean 2.9 days) [10]. The longer the CSF remains positive in neonates, the greater the chance of neurologic deficits in the survivors [10,11].
Antimicrobial therapy — Effective antimicrobial therapy for gram-negative bacillary meningitis is limited by several factors. These include [13,14]:
●The frequency of antibiotic resistance
●The poor diffusion of many antibiotics with activity against gram-negative pathogens into the subarachnoid space
●A high frequency of serious coexisting comorbidities
●The absence of intrinsic opsonic and bactericidal activity of CSF
Intravenous antibiotic therapy is the standard of care for gram-negative bacillary meningitis. Bacterial meningitis should be treated with an antibiotic agent that penetrates the CSF in adequate concentrations to exhibit bactericidal activity against the responsible pathogen [15] (see "Initial therapy and prognosis of bacterial meningitis in adults"). Patients with gram-negative bacillary meningitis who are treated with bacteriostatic antibiotics have poor clinical outcomes [16]. Bactericidal activity of antibiotic therapy in the CSF is affected by the penetration, concentration, and intrinsic activity of the drug [17]. The minimum concentration of a drug in the CSF needed for bactericidal activity is controversial [17]. We agree with authorities who advocate that selected antibiotic regimens should achieve CSF levels 10 or more times above the minimum bactericidal concentration (MBC) of the organism [18]. (See 'Choice of antimicrobial drugs' below.)
Intrathecal or intraventricular therapy (with aminoglycosides, colistin, or polymyxin B) is sometimes used concomitantly with intravenous therapy [19,20]. These invasive methods of delivery overcome the problem of poor penetration of both aminoglycosides and colistin into the CSF [21]. Guidelines from the Infectious Diseases Society of America (IDSA) recommend that dosages and intervals of intraventricular antimicrobial therapy should be adjusted to achieve CSF antimicrobial concentrations of 10 to 20 times the minimum inhibitory concentration (MIC) of the causative microorganism [22]
Of note, these local methods of delivery were ineffective in neonates and were also associated with poorer outcomes when compared with intravenous therapy in some older studies [17,19].
Duration — There are no comparative studies that examine the impact of duration of treatment in patients with gram-negative meningitis on outcome [17]. We recommend at least 21 days of therapy because high rates of relapse occur in patients treated with shorter courses [19,23]. However, the length of therapy ultimately should be tailored to the observed response of individual patients.
The CSF should be reanalyzed after the commencement of therapy to assess response. There are no definitive published data on the ideal timing of repeat LP. Since the average duration of therapy needed to sterilize the CSF in adults is two to four days [11], we suggest that the CSF be resampled after four to five days of therapy. In patients with repeatedly positive CSF cultures on appropriate antimicrobial therapy, treatment should be continued for 10 to 14 days following the last positive culture [22].
Role of dexamethasone — Dexamethasone is not warranted for management of raised intracranial pressure and of the inflammation associated with gram-negative bacillary meningitis, given the lack of evidence for benefit and risk of toxicity [24].
Although treatment of raised intracranial pressure and of the inflammation associated with bacterial meningitis with dexamethasone improves the neurologic outcome in selected children and adults, trials have not generally included patients with gram-negative infections. Caution should be exercised regarding use of dexamethasone for types of meningitis where no beneficial effect has been found [25].
Human studies on the benefit of adjunctive steroid therapy in patients with gram-negative meningitis are not likely to be performed for multiple reasons: (1) gram-negative meningitis is uncommon, and (2) affected patients often have co-morbid conditions that are either confounding and/or could be adversely affected by dexamethasone therapy. (See "Dexamethasone to prevent neurologic complications of bacterial meningitis in adults" and "Bacterial meningitis in children: Dexamethasone and other measures to prevent neurologic complications", section on 'Dexamethasone'.)
CHOICE OF ANTIMICROBIAL DRUGS — Until expanded-spectrum cephalosporins became available, the treatment of gram-negative bacillary meningitis relied mainly upon parenteral chloramphenicol [15] or direct instillation of antimicrobials into the central nervous system (CNS) [11,26]. Relapses and chronicity were common with gram-negative bacillary meningitis until highly active cephalosporins were first released [12].
Cephalosporins
Third generation — Broad-spectrum cephalosporins have been the treatment of choice for gram-negative bacillary meningitis since the late 1980s [27,28]. These antibiotics have good in vitro activity against gram-negative pathogens and they penetrate extremely well into the cerebrospinal fluid (CSF) [17]. Clinical outcomes improved remarkably since their introduction; success rates of 85 to 90 percent were reported in selected studies when these drugs were initially used [17]. As an example, ceftazidime is effective in treating meningitis due to Pseudomonas aeruginosa (cure rate 70 to 75 percent, with or without concomitant systemic aminoglycoside therapy) [17].
However, third-generation cephalosporins have limited role for CNS infections due to Enterobacter, Serratia, Pseudomonas (other than ceftazidime), and Acinetobacter. In one study, third-generation cephalosporins also did not reduce the mortality rate in cases of Klebsiella pneumoniae meningitis [8].
Nine percent of patients with gram-negative bacillary meningitis had isolates resistant to third-generation cephalosporins in one series of patients treated over a 12-year period [29]. In another series of patients treated over a six-year period, 25 percent of isolates were resistant to third-generation cephalosporins [30]. The authors noted an increase in resistance to these drugs from 1994 onwards. Cephalosporin-resistant pathogens included Acinetobacter baumannii, K. pneumoniae, Citrobacter freundii and Morganella morganii. These authors cautioned that third-generation cephalosporin resistance should be highly suspected in cases of nosocomially-acquired post-neurosurgical gram-negative meningitis.
In addition to the problem of innate resistance, the emergence of resistance to multiple beta-lactam antibiotics occurred in 14 to 56 percent of patients infected with gram-negative bacilli that possess inducible beta-lactamases [29]. This type of secondary resistance to beta-lactam agents was present in 30 percent of cases of meningitis due to Enterobacter in a case series [2]. In addition, a case report has highlighted the management challenge of nosocomial meningitis due to ESBL-positive K. pneumoniae [31]. As a result of the above observations, monotherapy with a third-generation cephalosporin should only be continued when the identity of the organism and its susceptibility patterns are known is known and secondary resistance is deemed to be unlikely to occur.
Serial testing for the emergence of resistance during therapy of gram-negative meningitis may be warranted even when initial in vitro susceptibility is documented. Such emergence of resistance during therapy is illustrated by a case report of two patients with Enterobacter cloacae meningitis who developed serial step-wise decreases in susceptibility to cephalosporins during treatment [32]. For this reason, some authors recommend that initial therapy for patients with gram-negative meningitis include an aminoglycoside plus a third-generation cephalosporin [32].
Fourth or later generation — The in vitro data on fourth-generation cephalosporins suggest that these drugs may have utility in the treatment of gram-negative meningitis. However, clinical data are limited.
●Cefepime – Cefepime is a fourth-generation cephalosporin with a gram-negative spectrum similar to that of ceftazidime, which includes Pseudomonas species [33]. Some organisms resistant to the third-generation cephalosporins remain susceptible to cefepime because it is less likely to be hydrolyzed by beta-lactamases [33]. Cefepime penetrates into the CSF as well as most third-generation cephalosporins (5 to 20 percent of serum levels [13]). Cefepime has been studied as a therapy for meningitis in children [33]. Cefepime resulted in a similar outcome and number of adverse events when compared with cefotaxime or ceftriaxone in the treatment of gram-negative meningitis due to susceptible organisms [33]. Concentrations of cefepime in the CSF varied from 55 to 95 times greater than the maximal minimum inhibitory concentration (MIC) required by the causative pathogens in one study of predominantly gram-positive bacteria [34].
●Cefpirome – Cefpirome has a broad range of in vitro antibacterial activity that includes Pseudomonas aeruginosa [35]. Cefpirome produces levels in the CSF that are 5 to 20 percent of the serum concentration of the drug [19]. The concentrations of drug in the CSF after a single intravenous dose are in excess of the reported MBCs for most pathogens responsible for community and hospital-acquired bacterial meningitis [35,36]. The CSF to serum concentration is also 11 to 49 percent of serum levels at two hours after a dose of cefpirome, and the antibiotic concentration after eight hours is still well in excess of the MBC for the most common gram-negative organisms that cause meningitis [36]. This agent is not available in the United States or Australia.
Ceftaroline is a fifth-generation cephalosporin with an in vitro activity similar to ceftriaxone but with improved gram-positive activity, including activity against methicillin-resistant Staphylococcus aureus, however, in the absence of clinical data, its use for gram-negative bacillary meningitis cannot be recommended. In an animal model of gram-negative meningitis, ceftaroline was more effective against Escherichia coli and K. pneumoniae than cefepime [37]. Ceftaroline is unsuitable for the treatment of extended-spectrum beta-lactamase (ESBL) producing bacteria and Acinetobacter, Pseudomonas, and Serratia spp [38].
Other drugs — There are a number of classes of antibiotics with substantial activity against gram-negative bacilli. A number of these drugs also penetrate into the cerebrospinal fluid (CSF). However, clinical data on the treatment of gram-negative bacillary meningitis with some of these agents are not extensive.
Aztreonam — Aztreonam is a monobactam that may be active against some aerobic gram-negative bacteria that cause gram-negative bacillary meningitis, including some strains of P. aeruginosa [39,40]. It is ineffective against anaerobic pathogens and gram-positive cocci.
Aztreonam has excellent CSF penetration into either inflamed or uninflamed meninges [40,41]. In an animal meningitis model, for example, the CSF penetration of aztreonam was 23 percent of serum levels, which is comparable to levels achieved with other beta-lactams in the same model [39,42]. A single-dose pharmacokinetic study [43] and a clinical trial in pediatric patients [42] demonstrated that aztreonam produced CSF levels that were 17 and 38 percent, respectively, of simultaneous serum concentrations. These levels are adequate for the treatment of meningitis caused by most gram-negative bacteria [42,43].
Clinical studies in both adults and children have demonstrated the efficacy of aztreonam in cases of meningitis caused by Serratia marcescens, K. pneumoniae, Enterobacter spp, Pseudomonas spp, Proteus mirabilis, E. coli, and M. morganii [40-42]. However, there were microbiologic and clinical failures reported in meningitis caused by Proteus vulgaris and Salmonella spp [40,42].
Carbapenems — Of the carbapenems, we generally prefer meropenem. It penetrates well into the CSF in the setting of inflamed meninges, shows good in vitro activity against many highly-resistant gram-negative bacilli, and has overall good efficacy in the treatment of meningitis in both children and adults [28,44-46].
Meropenem therapy is indicated for the treatment of nosocomial infections of the CNS caused by multiresistant gram-negative bacilli, such as ESBL producing organisms, Serratia, Enterobacter, and Acinetobacter, if isolates demonstrate in vitro susceptibility [22,44,47]. Meropenem may also be useful in the treatment of meningitis caused by P. aeruginosa when other treatments have failed [28,47]. There is also evidence that prolonged infusion of meropenem (each dose administered over three hours) may be successful in treating resistant gram-negative organisms [22]. (See "Prolonged infusions of beta-lactam antibiotics".)
Despite good in vitro activity, meropenem therapy can fail because of the emergence of resistance during therapy. As an example, there are reports of the appearance of resistance to meropenem during the treatment of meningitis caused by Acinetobacter [48]. (See "Acinetobacter infection: Treatment and prevention", section on 'Meningitis'.)
Imipenem also penetrates the CSF well, has a broad in vitro spectrum of activity, and good clinical efficacy [29,44-46,49]; however, its use has been limited by its potential to cause seizures. In one study of pediatric patients with meningitis treated with imipenem, 33 percent developed seizure activity following drug administration [50]. In addition, imipenem resistance has appeared during the treatment of meningitis due to P. aeruginosa [49].
Seizures have also been reported with ertapenem when used in the setting of CNS disorders [51]. Moreover, ertapenem has a narrower spectrum than either meropenem or imipenem and is not active against P. aeruginosa or Acinetobacter spp.
Another source of concern is the emergence of carbapenem-resistant K. pneumoniae [52]. These isolates are also resistant to all beta-lactam antibiotics and most are resistant to aminoglycosides and fluoroquinolones. In addition, detection of carbapenem resistance in some of these organisms is difficult if automated susceptibility testing systems are used [53]. (See "Overview of carbapenemase-producing gram-negative bacilli".)
Trimethoprim-sulfamethoxazole — Trimethoprim-sulfamethoxazole (TMP-SMX) penetrates well into the CSF and has bactericidal activity in vitro against numerous gram-negative organisms responsible for causing meningitis [13]. Many species of Klebsiella, Enterobacter, Serratia, Citrobacter, and Salmonella are susceptible in vitro to TMP-SMX [13]. However, some gram-negative bacilli are not killed by TMP-SMX. Consistent bactericidal activity, for example, has not been shown against Klebsiella or Providencia, and treatment failures have been reported [15].
TMP-SMX is a valuable treatment option, especially in cases of meningitis caused by gram-negative bacilli such as Salmonella, Acinetobacter calcoaceticus, Burkholderia cepacia, or Flavobacterium meningosepticum, which are often resistant to third-generation cephalosporins [15]. Therapy with TMP-SMX may also be indicated for patients with meningitis caused by gram-negative bacilli that are only moderately sensitive to cephalosporins [15], or by organisms that have the propensity to acquire resistance to cephalosporins via an inducible beta-lactamase [2]. This latter group includes Enterobacter, for which cefotaxime treatment failures have been reported [15]. Enterobacter meningitis has been successfully treated with TMP-SMX, which was a more effective therapy than the cephalosporins in one review [2].
In vitro studies suggest synergy between TMP-SMX and aminoglycosides against gram-negative bacilli [15]. Thus, occasionally these drugs may be useful in combination.
It is noteworthy that the use of TMP-SMX for prophylaxis of Pneumocystis jirovecii pneumonia (PCP) in patients with human immunodeficiency virus (HIV) infection or other types of immunosuppression may cause various body sites to become colonized with resistant species of organisms, such as Pseudomonas. Thus, TMP-SMX is not a good choice for empiric therapy in individuals with gram-negative bacillary meningitis who are currently, or were recently, taking this drug [54].
Aminoglycosides — Aminoglycosides penetrate the blood-brain barrier poorly [12], and do not usually achieve sufficient concentrations in the CSF to kill meningeal pathogens when administered parenterally [7,19]. Parenteral aminoglycosides are useful only when given with another bactericidal drug that penetrates the CSF well [18]. For this reason, they are usually combined with a third-generation cephalosporin, especially for treatment of fastidious gram-negative microorganisms [19]. Although gentamicin is most often used, tobramycin or amikacin can be substituted if either is substantially more potent in vitro than gentamicin.
Intrathecal plus simultaneous intravenous therapy with aminoglycosides can be used to treat gram-negative bacillary meningitis resistant to cephalosporins [48]. However, intrathecal administration of aminoglycosides has been associated with high mortality rates in neonates [17,55], and in another study, the mortality rate of patients given intraventricular aminoglycoside therapy was higher than that of patients given intravenous aminoglycoside therapy [56]. More recently, a nonrandomized observational study that evaluated the efficacy of a combination of various intravenous antimicrobial agents plus intraventricular gentamicin therapy in 13 of 31 consecutive patients with gram-negative meningitis seen at a single medical center suggested that combination therapy was superior to intravenous antimicrobial therapy [57]. The group of 13 patients treated with combination therapy had a higher cure rate (p = 0.03) and a lower relapse rate (0 of 13 versus 6 of 18). (See 'Intrathecal and intraventricular therapy' below.)
Ciprofloxacin and other quinolones — Fluoroquinolones are highly active in vitro against most gram-negative organisms that cause meningitis [58]. The use of ciprofloxacin in the treatment of meningitis has been the topic of several reviews [59-61]; ciprofloxacin or pefloxacin therapy was curative in more than 50 cases of meningitis to date [61]. There have also been case reports describing the successful use of ciprofloxacin in neonates with meningitis caused by multiply resistant gram-negative bacilli, in some of these cases ciprofloxacin concentrations in the CSF exceeded 50 percent of serum concentrations [60]. An early review of ciprofloxacin for the treatment of gram-negative bacillary meningitis in adults reported a 90 percent cure rate (18 out of 20 patients), with rapid sterilization of the CSF [59].
Despite such promising results, a decision to use ciprofloxacin in the treatment of gram-negative bacillary meningitis should be based upon the MIC of the causative pathogen, since this antibiotic has variable penetration into the CSF [59]. As an example, compared with serum concentration, the mean concentration of ciprofloxacin in the CSF was 8 and 37 percent, respectively, in patients with uninflamed and inflamed meninges [60]. In other studies, ciprofloxacin and ofloxacin reached 11 to 50 percent of serum concentrations in the CSF [61]. As a result of these data, we and others advise caution in the use of fluoroquinolones in the treatment of gram-negative bacillary meningitis. (See "Fluoroquinolones".)
Fluoroquinolones may be useful in selected patients with infections due to organisms that are resistant to beta-lactam antibiotics. As an example, 10 of 12 neonates and infants (83 percent) in one study of nosocomial meningitis were cured with ciprofloxacin after failing previous therapy [58]. In addition, success has been reported in the treatment of P. aeruginosa meningitis with ciprofloxacin [62].
There are limited data available on the efficacy of newer quinolones, such as moxifloxacin, in gram-negative bacillary meningitis. Moxifloxacin is reported to achieve CSF concentrations up to 80 percent of serum levels, based on data from patients with tuberculous meningitis [19,63]. In light of the paucity of clinical data associated with its use, we believe moxifloxacin should be reserved for the treatment of multiresistant isolates and used only by physicians who are familiar with its pharmacokinetics, dosing, and in vitro activity [19].
Chloramphenicol — Therapy with chloramphenicol for the treatment of meningitis caused by susceptible organisms (such as E. coli and Klebsiella) has a high failure rate and is associated with an increase in mortality [7]. These high failure rates are probably due to the fact that chloramphenicol has a bacteriostatic mechanism of action [15]. Despite high concentrations of chloramphenicol in CSF, the enteric pathogens may persist because the levels of drug are still below the minimum bactericidal concentration (MBC) required to kill the infecting organisms [7]. Chloramphenicol-resistant organisms also may emerge during therapy [14]. For these reasons, other more effective drugs have replaced chloramphenicol as a first-line therapy for gram-negative bacillary meningitis. Chloramphenicol use should be reserved for very few clinical scenarios, including adjunctive therapy along with other agents in the treatment of a multiply-resistant organism, infections for which alternative therapies are not available, or cases where an oral agent is required.
Tigecycline — Tigecycline is active against most Enterobacteriaceae, including ESBL producing species, A. baumannii, AmpC-, serine carbapenemase- and metallo-beta-lactamase (MBL) producing organisms. Some strains of E. coli, K. pneumoniae, M. morganii, and Proteus mirabilis have reduced susceptibility to tigecycline, but this may be overcome by combining tigecycline with other agents.
However, the role of tigecycline in gram negative bacillary meningitis is limited, since tigecycline CSF penetration is only 11 percent of serum levels, and the CSF concentrations after intravenous administration have been shown to not reliably exceed the MICs of most A. baumannii strains [64,65]. Also, nausea and/or vomiting associated with this agent is considerable [66]. Nevertheless, tigecycline, when in combination with other agents, has been successfully used to treat meningitis caused by multidrug resistant Acinetobacter spp. [67], and high-dose tigecycline was successful in a report of meningitis due to multi-resistant K. pneumoniae despite drug concentrations in the CSF that did not exceed the minimum inhibitory concentration of the infecting pathogen [68].
Ampicillin-sulbactam — There are little clinical data on the treatment of meningitis with ampicillin-sulbactam. The combination is effective in the treatment of bacterial meningitis caused by Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidis, and Staphylococcus species in infants, children, and adults [69,70]. Furthermore, sulbactam demonstrates in vitro activity against A. baumannii, including some carbapenem-resistant strains, and is therefore of potential use in meningitis caused by this organism.
The fraction of the serum concentration that appears in the CSF following administration has ranged from less than 1 percent in patients without meningitis to 33 percent in patients with meningitis [71].
INTRATHECAL AND INTRAVENTRICULAR THERAPY — We do not typically employ intrathecal (IT) or intraventricular (IVT) administration of antibiotics for the routine treatment of gram-negative bacillary meningitis. However, it remains a reasonable option for adjunctive therapy to intravenous antibiotics in children and adults with infections due to multidrug resistant organisms or infections refractory to appropriate parenteral therapy (ie, failure to sterilize the cerebrospinal fluid [CSF] after five to seven days of treatment). Careful calculation of dose and careful attention to the diluents used to administer IT or IVT therapy are critically important issues when antibiotics are given through these routes. Guidelines from the Infectious Diseases Society of America (IDSA) recommend that dosages and intervals of IVT antimicrobial therapy be adjusted to achieve CSF antimicrobial concentrations of 10 to 20 times the minimum inhibitory concentration (MIC) of the causative microorganism (table 1) [22].
Of note, determining the correct dosing regimen is challenging. CSF concentrations obtained with the same IVT dose have been highly variable in pharmacokinetic studies, likely because of individual differences in volume of distribution, ventricular size, or CSF clearance as a result of CSF drainage [22].
The utility and relative safety of IT or IVT antibiotics have been demonstrated in several small series in children and adults [20,21,23,27,72-74]. In a study of 34 post-neurosurgery patients with meningitis and ventriculitis, CSF cultures became negative within 48 hours after the administration of IT or IVT antibiotics in 23 patients (68 percent) [72]. The mean time to CSF sterilization was three days overall (range 1 to 12 days) and 6.5 days among the subset of patients with ventriculitis. A retrospective study from China of gram-negative bacillary meningitis described 14 patients who received IVT antimicrobial therapy because of persistently positive CSF cultures after an average of 25 days of intravenous antibiotics [73]. The mean time required to sterilize the CSF after appropriate IVT antibiotic treatment was 6.6 days. Despite the fact that many of these patients had infections due to highly drug-resistant pathogens, 11 out of 15 (73 percent) of patients were judged to be clinically cured.
Overall, there is little evidence to support the use of IT or IVT antibiotics in neonates [55,75]. However, individualized dosing of aminoglycosides through an IVT reservoir to maintain the concentration of the drug in CSF well above the MIC for the infecting organism at all times may lead to better outcomes among neonates [76].
Aminoglycosides, colistin, and polymyxin B are the only agents relevant for the treatment of gram-negative bacillary meningitis that are available for IT or IVT administration (table 1). There is little published evidence to help guide the choice between IT or IVT administration. However, it may be difficult to deliver adequate drug concentrations throughout the ventricular system through the IT route [77]. With aminoglycosides, at least, IVT administration achieves high antibiotic concentrations throughout the subarachnoid space and is thus superior to IT therapy if a system for administration is in place [12]. IVT aminoglycosides can be administered via an external ventricular drainage system, such as an Ommaya reservoir [27]. When antimicrobial therapy is administered via a ventricular drain, the drain should be clamped for 15 to 60 minutes to allow the agent to equilibrate throughout the CSF [22].
For treatment of ventriculitis, which accompanies gram-negative bacillary meningitis in more than 70 percent of cases [27], intravenous antibiotics should be given simultaneously if IVT antibiotics are used [78,79].
Management with IT or IVT antibiotics should be undertaken in consultation with specialists in infectious disease and neurosurgery. It may also be useful to enlist input from a pharmacist who can ensure that the chosen dose and the diluents used for administration are appropriate.
Gentamicin — When gentamicin is given via the IT or IVT route, it should be administered as a 0.2 to 0.5 percent solution (2 to 5 mg/mL), prepared by diluting the parenteral solution of drug in preservative-free normal saline [12,26,78]. The starting dose should be 1 to 5 mg every 18 to 24 hours, in conjunction with parenteral gentamicin (table 1) [12,14,26,78,80]. It is thought that concurrent parenteral gentamicin is necessary to provide a gradient to maintain CSF levels of intrathecally instilled gentamicin, although evidence to support this is limited. If CSF cultures are positive after 36 hours of therapy, the IT dose can be increased to 8 to 12 mg every 24 hours [26]. If a system is in place, IVT administration of gentamicin is superior to IT administration [12]. IVT gentamicin doses of 4 to 10 mg daily have been described in the literature [81].
When instituting this type of invasive therapy, scrupulous aseptic technique in the administration of the drug is very important. In addition, careful monitoring of CSF levels of aminoglycoside has been recommended, since the level of drug in the CSF can vary widely from patient to patient after administration of a fixed dose [14,26]. In a systematic review of studies of IVT aminoglycosides, therapeutic drug monitoring was reported in several studies, but the timing of CSF concentration measurements varied; nevertheless, no clear relationship between CSF levels and efficacy or toxicity was evident [81].
Colistin and polymyxin B — IT or IVT colistin (also known as polymyxin E) and polymyxin B have been used alone or in combination with systemic antibiotics with some success and without considerable adverse effects in cases of meningitis due to multidrug resistant gram-negative bacilli [20,21,73,74,79,82-88]. The optimal dosing is uncertain given variable dosing used in the literature (table 1). Guidelines from the IDSA recommend a daily IT or IVT dose of 10 mg colistimethate sodium (CMS), which is equivalent to 125,000 international units CMS or 4.2 mg colistin base activity; cumulative doses above 1,750,000 international units CMS (which correspond to the recommended daily dose for 14 days) have been associated with better outcomes [21,22]. Differences in the available drug formulations between different parts of the world may contribute to confusion around dosing and conversion of units [89]. Dosing of colistin administered should be assessed carefully, potentially in consultation with a pharmacist. (See "Polymyxins: An overview", section on 'Dosing and administration'.)
The optimal approach to IVT administration of colistin is uncertain as well; if antibiotics are administered through an IVT drain, IDSA guidelines recommend clamping the drain for 15 to 60 minutes [22]. A small number of case reports suggest clamping the tubing for one hour after administration to prevent dilution if there is a large volume of CSF drainage [87,88,90].
The efficacy of IT or IVT colistin is illustrated by the following observational studies:
●In a review of 83 cases of IT or IVT colistin used for multidrug resistant A. baumannii, all cases were post-neurosurgery [74]. The median daily colistin dose was equivalent to 4.2 mg colistin base activity (125,000 international units CMS) and the median duration of administration was 23 days, although for both the range was broad. Successful clinical and bacteriologic responses were reported in 89 percent. (See "Acinetobacter infection: Treatment and prevention", section on 'Meningitis'.)
●In another study of 18 patients with extensively drug resistant A. baumannii, use of IT/IVT colistin in addition to intravenous colistin was associated with a higher rate of CSF sterilization (100 versus 33 percent with intravenous colistin alone) [79]. The addition of IT/IVT colistin to intravenous colistin has also been associated with reduced mortality in hospital-acquired meningoventriculitis [83].
●IT colistin (equivalent to 4.2 mg colistin base activity daily [125,000 international units of CMS] in one or two divided doses) alone successfully treated two patients with ventriculoperitoneal shunt infections due to P. aeruginosa strains that were resistant to other antimicrobial agents [85].
IT therapy appears to lack the nephrotoxicity of intravenous colistin. However, IT and IVT colistin may be complicated by aseptic chemical meningitis or ventriculitis requiring dose reduction as the CSF white blood cell count increases [87]. Of note, the selection of colistin-resistant strains of A. baumannii during treatment has been observed in a patient with post-neurosurgical meningitis [91].
Amikacin — IT or IVT amikacin is rarely used because of the potential for ototoxicity and nephrotoxicity; thus it is usually a last resort for patients who have failed other therapies. IVT amikacin doses of 5 to 50 mg daily have been reported in the literature (table 1) [81].
Intrathecally administered amikacin enables higher CSF drug concentrations than those achieved with intravenous administration [27]. Amikacin administered intravenously achieves CSF concentrations 15 to 25 percent of serum concentrations, but such concentrations usually are below the MIC of the infecting organism.
TREATMENT RECOMMENDATIONS — Because much of the published experience with the treatment of gram-negative bacillary meningitis takes the form of case reports or small case series or is based mostly upon pharmacokinetic and in vitro data, we have formulated the following recommendations based upon our experience and a thorough review of the available literature.
Empiric therapy — Empiric therapy should include coverage for gram-negative bacilli in the following clinical scenarios:
●Clinical evidence of meningitis in a patient at risk for gram-negative central nervous system (CNS) infections (eg, patients with head trauma, neurosurgery, or a history of alcoholism, and neonates). (See "Gram-negative bacillary meningitis: Epidemiology, clinical features, and diagnosis", section on 'Epidemiology'.)
●Patients with cerebrospinal fluid (CSF) Gram stain revealing gram-negative bacilli when culture results are not available.
Specific empiric antibiotic regimens for patients with suspected acute bacterial meningitis and a high risk of gram-negative infection are discussed elsewhere:
●(See "Infections of cerebrospinal fluid shunts and other devices", section on 'Antibiotic therapy'.)
●(See "Bacterial meningitis in the neonate: Treatment and outcome", section on 'Empiric therapy'.)
Directed treatment — When culture results are already known, the following applies:
●Broad spectrum cephalosporins, such as cefotaxime (2 g IV every four to six hours) or ceftriaxone (2 g IV every 12 hours), are most appropriate for Enterobacteriaceae. If the organism is known to have inducible beta-lactamase production, use meropenem (2 g IV every eight hours) or trimethoprim-sulfamethoxazole (15 to 20 mg/kg per day divided every six to eight hours based upon the trimethoprim component) or both.
●A single active antipseudomonal agent, preferably ceftazidime (2 g IV every eight hours) or cefepime (2 g IV every eight hours), can be used for meningitis due to P. aeruginosa as long as the isolate tests susceptible to these agents. The addition of an aminoglycoside is not necessary.
●For organisms resistant to cephalosporins (eg, if it produces an extended-spectrum beta-lactamase), meropenem (2 g IV every eight hours) can be used if the organism is susceptible. Other alternatives, such as aztreonam, ciprofloxacin, or trimethoprim-sulfamethoxazole, can be chosen based upon susceptibility testing [19].
●For carbapenem-resistant organisms, meropenem plus either colistin or tigecycline can be used for cases if the minimal inhibitory concentration (MIC) with meropenem is ≤8 mg/L. However, in cases of higher level resistance (MIC >8 mg/L), therapeutic options, based on limited data, include ceftazidime-avibactam with or without an aminoglycoside and two or more drug combinations of colistin, tigecycline, and/or amikacin [92-95]. Data are even more limited on meropenem-vaborbactam for CNS infections, and we do not use it for this indication. (See "Overview of carbapenemase-producing gram-negative bacilli", section on 'Treatment'.)
Dual therapy should be used for patients with persistently positive CSF cultures on therapy. Intrathecal (IT) or intraventricular (IVT) therapy with gentamicin or polymyxins (table 1) are reasonable options for patients with meningitis due to organisms resistant to the above agents, when therapy with the above agents has failed to sterilize the CSF after five to seven days of therapy, and as adjunctive therapy in the case of coexisting ventriculitis with a multidrug-resistant organism. (See 'Intrathecal and intraventricular therapy' above.)
Adjuvant dexamethasone — Because of the lack of evidence of benefit and concerns about possible toxicity, dexamethasone is not recommended in adults with gram-negative bacillary meningitis [24]. (See 'Role of dexamethasone' above and "Dexamethasone to prevent neurologic complications of bacterial meningitis in adults".)
Use of dexamethasone in children with Haemophilus influenzae meningitis is discussed in detail separately. (See "Bacterial meningitis in children: Dexamethasone and other measures to prevent neurologic complications", section on 'Dexamethasone'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bacterial meningitis in adults" and "Society guideline links: Bacterial meningitis in infants and children".)
SUMMARY AND RECOMMENDATIONS
●Nosocomial gram-negative bacillary meningitis in adults occurs mainly in the setting of head trauma, neurosurgical procedures, a neurosurgical device, or cerebrospinal fluid (CSF) leak. Gram-negative bacilli, however, remain an uncommon cause of community-acquired bacterial meningitis in adults. In contrast, E. coli is a common pathogen in early neonatal meningitis. (See 'Introduction' above and "Gram-negative bacillary meningitis: Epidemiology, clinical features, and diagnosis", section on 'Epidemiology'.)
●Bacterial meningitis should be treated with an antimicrobial agent that penetrates the CSF in adequate concentrations to exhibit bactericidal activity against the responsible pathogen. Third-generation cephalosporins penetrate well into the CSF, and clinical experience with these agents in the treatment of meningitis is relatively extensive. However, innate and emerging resistance of gram-negative bacilli to this class of drugs may limit its widespread utility. (See 'Choice of antimicrobial drugs' above and 'Cephalosporins' above.)
●Fourth-generation cephalosporins, aztreonam, carbapenems, and trimethoprim-sulfamethoxazole are other agents for which there are less clinical data available but which nevertheless may be useful if the gram-negative organism retains susceptibility. Intravenous aminoglycosides are useful only when given with another drug that penetrates the CSF well. Other agents should be used with caution or only if no other options exist: CSF penetration of fluoroquinolones can be variable, tigecycline poorly penetrates the CSF, and chloramphenicol has a high failure rate. (See 'Other drugs' above.)
●Empiric therapy for suspected acute bacterial meningitis should include coverage for gram-negative bacilli in patients at risk for gram-negative central nervous system (CNS) infections (eg, patients with head trauma or neurosurgery, immunosuppressed patients, alcoholics, or neonates) or in those who have a CSF Gram stain that reveals gram-negative bacilli. We use ceftriaxone or, if Pseudomonas is suspected, ceftazidime. The empiric therapy of suspected acute bacterial meningitis in various populations is discussed in detail elsewhere. (See 'Empiric therapy' above and "Bacterial meningitis in the neonate: Treatment and outcome", section on 'Empiric therapy' and "Infections of cerebrospinal fluid shunts and other devices", section on 'Antibiotic therapy' and "Initial therapy and prognosis of bacterial meningitis in adults".)
●Once the organism is identified, directed antimicrobial therapy should be based on susceptibility patterns, including whether the organism is known to have inducible beta-lactamase production or is suspected of producing an extended-spectrum beta-lactamase. (See 'Directed treatment' above.)
●Despite appropriate therapy and an apparent clinical response, CSF cultures may remain positive for several days; the average duration of therapy needed to sterilize the CSF is two to four days in adults and three to eight days in neonates. In adults, we typically resample CSF again after four to five days of therapy to evaluate for sterilization. Repeat lumbar puncture in neonates with gram-negative bacillary meningitis is discussed elsewhere. (See 'General principles for treatment' above and "Bacterial meningitis in the neonate: Treatment and outcome", section on 'Repeat lumbar puncture'.)
●Aminoglycosides, colistin, and polymyxin B can be administered via the intrathecal or intraventricular route (table 1) and often retain activity against resistant gram-negative bacilli, but their use in this manner is generally restricted to meningitis and ventriculitis due to multidrug resistant organisms or cases in which therapy with the intravenous agents has failed to sterilize the CSF after five to seven days. Doses and dosing intervals of intraventricular therapy should target CSF concentrations of 10 to 20 times the minimum inhibitory concentration (MIC) of the causative organism. (See 'Intrathecal and intraventricular therapy' above.)
●Dexamethasone is not warranted for management of raised intracranial pressure and of the inflammation associated with gram-negative bacillary meningitis, given the lack of evidence for benefit and risk of toxicity. (See 'Adjuvant dexamethasone' above.)
●We typically treat gram-negative bacillary meningitis in adults for at least 21 days because high rates of relapse occur in patients treated with shorter courses. However, the length of therapy ultimately should be tailored to each individual patient, taking into account factors such as the underlying risk factors for infection, the infecting organism, the antimicrobial susceptibilities, the agent used, and the clinical response. Treatment duration of gram-negative bacillary meningitis in neonates is discussed in detail elsewhere. (See 'Duration' above and "Bacterial meningitis in the neonate: Treatment and outcome", section on 'Escherichia coli and other gram-negative organisms'.)
