59 Acinetobacter Infections: An Emerging Problem in the Neurosurgical Intensive Care Unit

A. Rodríguez-Guardado ¹, A. Blanco ², F. Pérez ³, M. Álvarez Vega ⁴, JM Torres ⁴, JA Cartón ¹

¹ Infectious Diseases Unit, Hospital Universitario Central de Asturias, Spain

² Intensive Care Unit, Hospital Universitario Central de Asturias, Spain

³ Microbiology Unit, Hospital Universitario Central de Asturias, Spain

⁴ Neurosurgery Unit, Hospital Universitario Central de Asturias, Spain

59.1 Introduction

Interest in Acinetobacter spp. has been growing for the past 30 years. One of the main reasons for the present increased interest in this genus is the emergence of multiresistant strains, several of which are pan-resistant to antibiotics and suddenly cause an outbreak of infection [1]. Some of these outbreaks of nosocomial infections have occurred in intensive care units (ICUs) where treatment and control are difficult.

Multidrug-resistant Acinetobacter baumannii is a rapidly emerging pathogen in the healthcare setting, where it causes infections including bacteraemia, pneumonia, meningitis, urinary tract infections, and wound infections. The associated mortality is high. The crude mortality rate associated with bacteraemia is approximately 52% and that associated with pneumonia ranges from 23 to 73% [2,3]. It is among the most difficult antimicrobial-resistant Gram-negative bacilli to control and treat due to its ability to survive under a wide range of environmental conditions and to persist for extended periods of time on surfaces, making it a frequent cause of outbreaks of infection and an endemic healthcare-associated pathogen.

Recently, an increased rate of infections caused by A. baumanii strains resistant to antibiotics traditionally used in therapy has been reported [3-5]. This is an especially severe event in such infections as post-surgical meningitis because the choice of an antibiotic depends not only on the sensitivity of A. baumanii but also on the antibiotic’s penetrability through the blood-brain barrier. Multidrug-resistance complicates the treatment of infection, making the search of new agents imperative and the return to old drugs for optimal treatment of this multidrug-resistant organism.

The focus of this review is to summarize the current state of knowledge regarding A. baumannii in relation to its taxonomy, identification, microbiology, epidemiology, infections, resistance to antibiotics, and the potential therapeutic approaches to postsurgical meningitis in particular.

59.2 Microbiological Characteristics

The genus Acinetobacter comprises ubiquitous Gram-negative bacilli that were originally identified in the 1930s [3,6]. Subsequently, several changes were introduced into the taxonomic classification of Acinetobacter spp. The genus Acinetobacter initially encompassed a heterogeneous collection of non-pigmented, oxidase-positive and oxidase-negative Gram-negative rods [3,6-8]. The genus Acinetobacter is now defined as including Gram-negative (but sometimes difficult to stain) coccobacilli, with a DNA G1C content of 39 to 47 mol%, that are strictly aerobic, nonmotile, nonfermentative, catalase-positive and oxidase-negative. Good growth occurs at 40°C without the need for growth factors, while nitrates are reduced only rarely [3]. It appears as bacilli during the rapid growth phase and as cocobacilli in the stationary phase [9].

Over 20 species belonging to the genus Acinetobacter have been identified [10]. A. baumannii (two genomic species) is the species of greatest clinical relevance, and it is typically associated with outbreaks in the hospital setting [11]. Other species that have been associated with disease in humans belong to the A. calcoaceticus-A. baumannii complex that includes three Acinetobacter genomic species: A. johnsonii, A. wolffii, and A. calcoaceticus subsp. anitratus [9].

59.3 Epidemiology

Increasing isolation of multidrug-resistant (MDR) A. baumannii has been reported worldwide, and it is now one of the most difficult nosocomially acquired Gram-negative pathogens to control and treat [12]. A. baumannii has the ability to utilise various sources of nutrition, which accounts for its growth on routine laboratory media. This explains its survival as an environmental pathogen. Some strains can survive environmental desiccation for weeks, a characteristic that promotes transmission through fomite contamination in hospitals [13]. The capacity of Acinetobacter spp. to survive on most environmental surfaces for long periods of time suggests that all animate and inanimate entities should be considered reservoirs.

In healthcare settings, colonized and infected patients are often the sources of A. baumannii infections; however, the ability of the organism to survive for prolonged periods on environmental surfaces has also contributed to protracted outbreaks in these settings [12]. Acinetobacter has been isolated from pasteurized milk, frozen foods, chilled poultry, foundry, and hospital air, vaporizer mist, tap water faucets, peritoneal dyalisate baths, bedside urinals, washcloths, door handles, keyboards, angiography catheters, ventilators, contaminated gloves, duodenoscopes, laryngoscope blades, plasma protein fraction, and hospital pillows [14-16]. This ability to grow on medical equipment and throughout the hospital environmental emphasizes the need for special attention to disinfection [17-20].

Multidrug-resistant Acinetobacter spp. infections have been described in patients admitted to rehabilitation centres and long-term care facilities, as well as in patients hospitalized for acute illnesses [21-26]. The origin of a particular epidemic strain of A. baumannii in a hospital is often unknown [21]. There are several factors that maintain the presence of Acinetobacter spp. in the healthcare environment, including the presence of susceptible patients or health workers colonized or infected by the microorganism. Acinetobacter spp. can colonize the skin, wounds, and the respiratory and gastrointestinal tracts. Up to 25% of healthy ambulatory adults exhibit cutaneous colonization and 7% of adults and children have transient pharyngeal colonization. It is the most common Gram-negative organism persistently carried on the skin of hospital personnel and it has been found to colonize 45% of inpatient tracheostomy sites and 41% of faecal samples in ICUs [22-23]. Differentiating between colonization and infection has clinical and therapeutic relevance because the presence of colonized or infected patients is important in maintaining the organism in the hospital. According to Landman et al. [27], 31-50% of patients admitted to ICUs have clinical samples testing positive for A. baumannii but only between 10-35% show clear signs of infection.

Acinetobacter baumannii can cause community-acquired infections although less frequently than nosocomial infections. Multidrug-resistant Acinetobacter infection has been reported among patients residing in rehabilitation and long-term care facilities, as well as in acute care hospitals [24-26]. Several factors maintain the presence of multidrug-resistant Acinetobacter spp. in the healthcare setting, including the presence of susceptible patients, the presence of patients already colonized or infected with the organism, selective pressure from antimicrobial use, and incomplete compliance with infection control procedures [28].

In addition to transmission, the emergence of resistance occurs in the context of selective pressure from broad-spectrum antimicrobial therapy with carbapenems or third-generation cephalosporins. The relative contribution of antimicrobial selective pressure and transmission between patients to the emergence of multidrug-resistant Acinetobacter spp. is not known [29-31].

59.4 Antimicrobial Resistance

Various terms have been used (sometimes interchangeably) to denote antimicrobial-resistant phenotypes of Acinetobacter spp. The most common definitions of multidrug resistance are carbapenem resistance or resistance to more than three classes of antimicrobials [32].

The emergence of multiresistance in Acinetobacter spp. complicates the choice of antibiotic treatment and is associated with significant morbidity (63.4%) and mortality (44.2%) [33]. The resistance rate varies between geographic areas, hospitals and even different hospital wards within the same hospital [34]. Some studies [35] found sensitivity rates of imipenem and amikacin of almost 74% in North America and Europe, 60% and 23%, respectively, in Latin America, and 69.2% and 59.6%, respectively, in the Asian region. According to the SENTRY study [36-38] involving 30 European centres from 2001 to 2004, the proportion of strains resistant to imipenem, meropenem, ampicillin-sulbactam and polymyxin B was 26.3%, 29.6%, 51.6%, and 2.7%, respectively. More recent data collected in the MYSTIC study (Meropenem Yearly Susceptibility Test Information Collection) involving 40 hospitals in 12 European countries showed higher rates of resistance to meropenen (43.4%) and imipenem (42.5%) [39]. These results may be even higher in ICUs where several studies have reported resistance to meropenem and imipenem of nearly 75-80% [40].

In several countries, the rate of resistance to colistin is now 2-3% in relation to previous use, and heteroresistant populations have emerged which can hinder its future use in monotherapy [41]. Although tigecycline once appeared to be a good alternative to conventional treatments, reports have increasingly described the emergence of resistant strains even during treatment with the drug, severely compromising its use in empirical therapy. A German study of 215 strains of A. baumannii found resistance rates to tigecycline of almost 6% compared to 2.8% for colistin [42]. Another recent study reported resistance rates of 25%, suggesting that the role of antibiotic therapy with these drugs should be carefully evaluated [40].

Several risk factors for the acquisition of multidrug-resistant strains have been identified. These include the previous use of antibiotic treatments, especially carbapenems and third-generation cephalosporins, followed by quinolones, aminoglycosides and metronidazole, and the number of previous antibiotics. The second most common risk factor is the use of mechanical ventilation. Other factors include a stay in the ICU, duration of ICU stay and overall hospital stay, severity of the underlying disease, recent surgery and invasive techniques [43,44]. Acinetobacter spp. display mechanisms of resistance to all existing antibiotic classes, as well as a prodigious capacity to acquire new determinants of resistance [45]. The capacity of Acinetobacter spp. to develop extensive antimicrobial resistance may be due in part to the organism’s relatively impermeable outer membrane and its environmental exposure to a large reservoir of genes.

59.4.1 Mechanisms of Resistance

Resistance mechanisms for Acinetobacter spp. generally fall into three categories: 1) antimicrobial-inactivating enzymes; 2) reduced access to bacterial targets; and 3) mutations that change targets or cellular functions. Because Acinetobacter spp. are Gram-negative organisms, they possess an additional outer membrane that acts as a permeation barrier [2,13,44].

59.4.2 Resistance to Beta-lactams

The mechanism of resistance to beta-lactams involves: 1) their hydrolysis by beta-lactamases; 2) changes in penicillin-binding proteins (PBPs) that inhibit their action; 3) alterations in the structure and number of porin proteins that result in decreased permeability to antibiotics through the outer membrane of the bacterial cell; and 4) the activity of efflux pumps that further decrease the concentration of an antibiotic within the bacterial cell [46,47].

The most important problem in multidrug-resistant Acinetobacter is its resistance to carbapenems. This resistance is mediated by various mechanisms:

• Metallo-β-lactamase (VIM, IMP).
  
• OXA carbapenemases (class D).
  
• Cell permeability changes.
  
• Target (PBPs) changes.

The metallo-β-lactamases and OXA carbapenemases are the most important mechanisms of resistance in A. baumannii because they confer resistance to carbapenems. These enzymes belong to either Ambler Class B (metallo-β-lactamases) or class D (oxacillinases) [48]. Metallo-β-lactamases are efficient carbapenemases. Three groups of this enzyme class have been found in Acinetobacter spp: IMP-like MBL, VIM-like MBL, and SIM-1. IMP and VIM confer high-level resistance to carbapenems and most other beta-lactams, with the exception of aztreonam. MBL are class-1 integrons and may be transferred and expressed along with resistance genes to other antimicrobials such as aminoglycosides [34,47,57-59].

The other group of enzymes (carbapenem-hydrolysing oxacillinases) consists of oxacillinases with intrinsic carbapenemase activity. The significant contribution of these enzymes to carbapenem resistance in A. baumannii has been emphasized, particularly when they are accompanied by ISAba1 and ISAba3 in the naturally occurring plasmid [60-62].

A third mechanism of carbapenem resistance involves porins, which are outer-membrane proteins that allow antimicrobials, such as beta-lactams, to permeate into the bacterial cell. Loss or modification of porin proteins has been shown to confer carbapenem resistance and high-level resistance is observed in the presence of both loss of porin function and expression and production of carbapenemases [47,63]. Another mechanism contributing to carbapenem resistance is the overexpression of bacterial efflux pumps that decrease the concentration of beta-lactam antibiotics in the periplasmic space [64]. Efflux pumps cause clinical resistance in Acinetobacter spp. by acting in association with the overexpression of AmpC beta-lactamases or carbapenemases. With less beta-lactam entering the periplasmic space, the weak enzymatic activity of beta-lactamase is amplified. Besides removing beta-lactam antibiotics, efflux pumps can actively expel quinolones, tetracyclines, chloramphenicol, disinfectants, and tigecycline [66,62,47].

Various factors associated with the emergence of strains resistant to carbapenems and sensitive to colistin have been identified, including prior exposure to quinolones and antipseudomonal drugs and the number of antibiotics used previously [65].

59.4.3 Resistance to Aminoglycosides

Resistance to aminoglycosides is mediated by three mechanisms: alteration of the ribosomal target; reduction of uptake; and enzymatic modification of the drug. Alteration of the ribosomal target only affects streptomycin. The second mechanism is fairly common in Acinetobacter spp., but resistance to aminoglycosides in A. baumannii is mediated principally by aminoglycoside-modifying enzymes. These include aminoglycoside O-phosphotransferases, aminoglycoside N-acetyltransferases, and aminoglycoside O-nucleotidyltransferases. They are mediated primarily by plasmids or transposons that can play a role in the spread of resistance. These enzymes may also be chromosomally located [3,67,68].

59.4.4 Resistance to Quinolones

Resistance of A. baumannii to quinolones is often caused by modifications in the structure of DNA gyrase secondary to mutations in the quinolone resistance-determining regions of the gyrA and parC genes [69,70]. These changes result in a lower affinity for the binding of quinolone to the enzyme-DNA complex. As mentioned above, a second mechanism of resistance to the quinolones is mediated by efflux systems that decrease intracellular drug accumulation [48].

59.4.5 Resistance to Tetracyclines

Two different mechanisms of resistance to tetracyclines have been described in A. baumannii. TetA and TetB are specific transposon-mediated efflux pumps; TetB determines the efflux of both tetracycline and minocycline, whereas TetA drives only the efflux of tetracycline. The second mechanism is the ribosomal protection protein, which shields the ribosome from the action of tetracycline. The tet(M) gene encodes this protein, which serves to protect the ribosome from tetracycline, doxycycline, and minocycline [3,46].

Tigecycline is the first antibiotic of a new class called glycylcyclines that may be useful for multidrug-resistant Acinetobacter [71-73]. Tigecycline overcomes the two major mechanisms of resistance to tetracyclines (ribosomal protection and efflux), but tigecycline resistance emerging during therapy has been reported [72]. This resistance appears to be attributable to overexpression of the AdeABC multidrug efflux pump [73]. Probably this mechanism can be upregulated by the previous use of other antibiotics (e.g., fluoroquinolones, aminoglycosides) that are administered frequently in patients with serious infections [74].

59.4.6 Resistance to Polymyxins

There are several suggested mechanisms of resistance to colistin/polymyxin B in Gram-negative bacteria, most of which involve changes in the outer membrane. The mechanism of resistance to colistin likely resides in modifications in the lipopolysaccharide of A. baumannii (acidification, acylation, or presence of antigens that interfere with the binding of the antibiotic to the cell membrane) [3]. A strong association has been reported between the use of colistin and the development of resistance in clinical isolates of A. baumannii [75].

59.5 Virulence and Pathogenicity

A. baumannii is regarded as a low-grade pathogen with limited virulence. However, this microbe has certain features that allow it to increase the virulence of those strains implicated in infections. The bacteria’s invasiveness may be related to substances that protect the surface of phagocytosis, i.e., the polysaccharide capsule. The presence of fimbriae allows adhesion to human epithelial cells. Studies have investigated the production of such enzymes as butyrate esterase, caprylate esterase, leucine and aryl amidase which may damage tissue lipids and the potentially toxic role of the lipopolysaccharide component of the cell wall and the presence of lipid A. Apart from sharing factors in common with other Gram-negative bacteria, Acinetobacter spp. produce a lipopolysaccharide that can exert an endotoxigenic effect through lipid A and that enhance the ability of these microorganisms to capture iron through the secretion of siderophores, which allows them to survive in the human body. Moreover, some strains of Acinetobacter spp. can produce slime which was considered to be the main factor responsible for the enhancement of virulence in mixed infections [1,3,76].

All these factors act together in the pathogenicity of Acinetobacter spp. The capsular polysaccharides and lipopolysaccharides (LPSs) act in synergy by blocking access of the human complement to the bacterial cell wall, thus preventing its lytic activity on bacterial membranes. Furthermore, the hydrophilicity conferred by the presence of capsular polysaccharides, together with other nonspecific adherence factors (i.e., fimbriae), prompts the colonization of human epithelial cells by pathogenic strains [77]. Enzymes able to damage tissue lipids are also produced during the infectious stages of colonization. Interestingly, the action of LPSs in the pathogenicity of Acinetobacter is not limited to the protection of bacterial cells from host defences; these molecules are, in fact, provided with a powerful endotoxic activity, and their production in vivo is thought to be related to Acinetobacter septicaemia symptoms [78,79].

59.6 Useful Antibiotics for Acinetobacter Infections

Distinct classes of antimicrobial agents considered potentially effective in the treatment of A baumannii infection include: sulbactam; antipseudomonal penicillins or cephalosporins; carbapenems; monobactams; aminoglycosides; fluoroquinolones; glycylcyclines; and colistin [80]. However, the emergence of strains with high resistance to carbapenems, aminoglycosides and fluoroquinolones [35,36,81] poses a challenge to the clinician; therefore, sulbactam, tigecycline and colistin represent the current therapeutic approaches associated with satisfactory efficacy.

59.6.1 Carbapenems

Imipenem and meropenem have been regarded as the treatment of choice for severe A. baumannii infections, although the increase in resistance rates of A baumannii isolates to carbapenems, especially in Europe and North America, have diminished their usefulness [35]. Furthermore, carbapenem-resistant A. baumannii strains might only rarely be susceptible to other antipseudomonal agents [80], making treatment very difficult.

As described above, carbapenem resistance in A. baumannii is mediated by several mechanisms, including plasmid or chromosomally encoded carbapenemases (mainly OXA-23-like, OXA-24-like, or OXA-58-like class D β-lactamases), as well as metallo-β-lactamases (class B β-lactamases), efflux pump mechanisms, penicillin-binding protein alterations, and modifications or loss of outer membrane proteins (porins) [48,80]. More than one of these resistance determinants could be present in the same strain, thus conferring it high-level resistance.

A recently developed carbapenem is Doripenem, a novel, forthcoming carbapenem that possesses a broad spectrum of activity against Gram-negative bacteria similar to that of meropenem, while retaining the spectrum of imipenem against Gram-positive pathogens [82]. It is approved for the treatment of complicated urinary tract and complicated intra-abdominal infections. An indication for hospital-acquired pneumonia including ventilator-associated pneumonia is pending. Its principal features are: 1) bactericidal action against most species; 2) β-lactamase stability to commonly occurring enzymes, including the emerging extended-spectrum β-lactamases (ESBLs); 3) pharmacokinetic and pharmacodynamic qualities similar to those of meropenem (half-life of 1 h) with minimal risk of convulsive adverse reactions; 4) postantibiotic effects of nearly 2 h in vitro for Pseudomonas aeruginosa; and 5) low serum protein binding (8.9%). Doripenem is stable enough in the presence of renal dehydropeptidase I that it need not be coadministered with a dehydropeptidase I inhibitor such as cilastatin. Pharmacokinetic studies have supported a 3-times-daily dosing schedule [83].

The most frequent adverse reactions are: nausea, diarrhoea, headache, phlebitis, hypersensitivity reaction, and C. difficile-associated colitis. In contrast to imipenem, doripenem did not cause electroencephalographic changes or seizures in animal studies [84-86].

Doripenem may be have a important role in the treatment of Acinetobacter infection because it has a lower minimum inhibitory concentration (MIC) than ertapenem or imipenem when tested against Acinetobacter spp. [85,86] and some isolates that are intermediate or resistant to other carbapenems may be susceptible to doripenem [85,86]. In a recent study 86 on 12,581 isolates collected between 2005 and 2006 and tested with doripenem, imipenem and meropenem, the MIC(90) of doripenem (0.12) was comparable to that of meropenem (0.12) and superior to that of imipenem (2), though the susceptibility of the isolates exceeded 99% for all evaluated carbapenems. Doripenem (MIC(90) = 2, 89.1%S) was twice as active at MIC(90) against imipenem-susceptible Acinetobacter spp. as imipenem or meropenem. However, none of the carbapenems was active against A. baumannii strains expressing plasmid-mediated carbapenemases [86,87].

59.6.2 Colistin

Colistin belongs to the Polymyxins group and is available in two forms, colistin sulphate and colistimethate sodium. Colistimethate sodium is a non-active prodrug that is hydrolyzed in vivo to the active form and used for parenteral administration due to its lower toxicity [89]. Polymyxins show bactericidal activity against A baumannii by interacting with anionic lipopolysaccharides on the bacterial cell membrane, leading to an increase in membrane permeability [36,90]. Resistance rates against these agents have remained low despite their more frequent use and the presence of carbapenem-resistant strains [37,91,92].

The usual dose of colistin is 2.5-5 mg/kg/day in 2 to 4 divided doses. In persons weighing >60 kg, the most frequent dose is 80-160 mg/8 h. Dose adjustment is required in the presence of renal failure. Since the bactericidal activity of colistin is concentration-dependent, administering large doses over less frequent intervals may be a favourable approach [93-97]. Isolated case reports described the cure of A. baumannii bacteraemia with continuous intravenous colistin (2,000,000 IU/24 h) in patients with allergic reactions to other treatment [96]. However, the emergence of heteroresistant strains with increasing frequency, along with the pharmacodynamic characteristics of the drug, appear to discourage their use in 24-hour intervals. Owen et al. [97] showed a rapid bactericidal concentration-dependent effect, with regrowth at 3 hours after administration that was clearly significant at 24 hours, even at concentrations 32 and even 64 times above the MIC in some isolates, which advises against its use as monotherapy, and at 24-hour intervals in the presence of heteroresistant strains.

Colistin alone or in combination with other antimicrobials like rifampicin demonstrated its usefulness in several infections due to A. baumannii such as ventilator-associated pneumonia, meningitis, and bacteraemia, with rates of clinical and microbiological response close to 80% and 95%, respectively, depending on the type of infection [98-102]

It has sometimes been used in nebulized form in variables doses, although the most common are 2-4 million IU with conventional intravenous treatment. The response rate was 85.7% after a single treatment. More studies are needed to clarify its role [103].

The most common toxic effects of colistin are nephrotoxicity and polyneuropathy. For this reason, the systemic administration of polymyxins was abandoned for about 20 years in most areas of the world. However, the problem of infections due to multidrug-resistant Gram-negative bacteria such as P. aeruginosa and A. baumannii has led to the re-use of polymyxins. Most non-comparative studies have reported an 8-21% rate of renal toxicity associated with polymyxin therapy which appears to be correlated with the cumulative dose, although recent studies using doses of 225 mg/8 h did not observe the occurrence of nephrotoxicity. Patients with pre-existing renal dysfunction in any stage including hemodiafiltration or hemodialysis seem to be more susceptible to the renal adverse effects of polymyxins [102,104-109]. However, a recent study by Hartzell et al. [110] reported a higher percentage of nephrotoxicity (45%), with interruption of therapy in 21% of patients. This study evaluated nephrotoxicity according to the RIFLE criteria (risk, damage, failure, loss and end stage renal disease), and the higher toxicity was possibly related to greater rigor in applying the criteria. Other side effects are neurotoxicity, bronchoconstriction, chest tightness or cough following administration via the respiratory tract. Chemical meningitis with intraventricular or intrathecal use has been infrequently reported [111-112].

Resistance to colistin is low but it has already been reported. The risk factors significantly associated with the isolation of colistin-resistant isolates were age, length of ICU stay, surgical procedures, use of colistin, use of monobactams, and duration of use of colistin. Although the use of colistin was identified as the only independent risk factor in the multivariable model [113]. To prevent this phenomenon, colistin should be used judiciously, given that treatment options for colistin-resistant Gram-negative bacteria are limited. However, in many occasions it must be used as empirical therapy. Falagas et al. [114] estimated that between 4 and 5 of 100 patients admitted to the ICU will die if colistin is not included in empirical antibiotic treatment. Colistin should probably be included as empirical antibiotic therapy in those ICUs where the probability of contracting a microorganism sensitive only to colistin is close to 50%.

59.6.3 Ampicillin-sulbactam

Sulbactam was introduced in the 1980s as a beta-lactamase inhibitor in combination with beta-lactamic antibiotics [4,5]. Sulbactam exerts its bacteriostatic activity against Acinetobacter spp. by binding to PBP2. The most frequently used combination is ampicillin/sulbactam (ratio 2:1), although the two agents are not synergetic [115-117]. The combination of ampicillin-sulbactam has been used by some authors in doses of 2 g/6-8 h [34,115]. The use of ampicillin/sulbactam had been described in retrospective series. Combination therapy has shown effectiveness similar to imipenem therapy in A baumannii ventilator-associated pneumonia or bacteraemia caused by multidrug-resistant drugs [115-122]. Favourable clinical outcomes have also been reported with sulbactam or combination ampicillin/sulbactam therapy in patients with other types of nosocomial infections like meningitis [101,121]. Therefore, ampicillin-sulbactam is a sensible option for the treatment of life-threatening Acinetobacter infections. However, the role of sulbactam in the treatment of Acinetobacter infections is limited due to the development of multidrug-resistant strains.

59.6.4 Glycylcyclines

Glycylcyclines are a novel class of antimicrobial agents related to the tetracyclines. Tigecycline was the first commercially available agent in this class. Tigecycline is a semisynthetic derivative of minocycline that arises from the incorporation of the t-butyl glycylamide radical in position 9 of minocycline, a structural change that enhances its spectrum and provides a better resistance profile. Its mechanism of action is like that of tetracycline: it inhibits protein translation by binding reversibly to the 30S subunit of the bacterial ribosome. This binding blocks the entry of aminoacyl t-RNA to the site of the ribosome, thus preventing the incorporation of amino acids and the subsequent formation of long-chain peptides [123-125]. Glycylcycline binds five times more effectively than tetracycline, which may affect its ability to overcome resistance to tetracyclines from the protection of the ribosome. Moreover, it seems that the mode of interaction of tigecycline with the ribosome is different from that of tetracyclines. It shows bacteriostatic activity against A baumannii because it interferes with bacterial protein synthesis through ribosomal binding and thus exhibits its time-dependent bactericidal activity.

Tigecycline is extensively distributed into many tissues, resulting in a prolonged half-life that justifies twice-daily dosing. Fifty-nine percent of a tigecycline dose is excreted through the liver, and 33% is excreted through the kidney. In patients with severe hepatic impairment (Child’s class C), the normal dose of tigecycline (100 mg initial dose, then 50 mg twice daily) should be reduced to 25 mg twice daily after the normal loading dose. No adjustments are required for any level of renal impairment [124].

Tigecycline is able to evade the most common mechanisms of resistance to tetracyclines in A baumannii, including efflux pumps encoded by the tet(A) and tet(B) determinants, and ribosomal protection mechanisms. Nevertheless, several unique multidrug efflux pumps have been shown to reduce the organism’s susceptibility to tigecycline and the rate of resistance is nearly 6% [126,127].

Clinical experience with the use of tigecycline for the treatment of patients with multidrug-resistant A baumannii infections is accumulating. Tigecycline has been used in a small number of critically ill patients – mainly as part of combination antibiotic regimens—for the treatment of various types of infections, including ventilator-associated pneumonia and primary or secondary bacteraemia [128-132]. In early case series, most patients had a good clinical outcome. However, the failure of tigecycline to clear A. baumannii bacteraemia was reported in a few cases [132]. Furthermore, pharmacokinetic and pharmacodynamic data indicate that tigecycline blood concentrations seem to be suboptimal for maximal antibacterial activity to be exerted in this compartment. There are increasing reports indicating that resistance to tigecycline developed during treatment. In a recent review of retrospective data on 42 severely ill patients, 31 of which had a respiratory tract infection (in 4 cases with secondary bacteraemia) and 4 had bacteraemia, tigecycline therapy (in combination with other antibiotics in 28 patients) was effective in 32/42 cases, but resistance developed in 3 cases during the treatment [128].

Clinicians should be aware that tigecycline MICs for A. baumannii isolates may increase during therapy after brief exposure to the drug. Patients receiving tigecycline for Acinetobacter infection should be monitored for the development of clinical resistance, and isolates should be monitored for evidence of microbiologic resistance.

59.6.5 Aminoglycosides

Aminoglycosides have shown moderate rates of antimicrobial activity against A baumannii. In worldwide collections of Acinetobacter spp. isolates, susceptibility rates to amikacin were approximately 60% [36] and the activity of aminoglycosides is lower for multidrug-resistant isolates of A baumannii compared with non-multidrug-resistant ones [133]. Reports on the clinical use of aminoglycosides in human beings are scarce and refer to cases of bacteraemia [134] or meningitis [101] in which aminoglycosides have been used in combination with other classes of antimicrobial agents.

59.6.6 Fluoroquinolones

Fluoroquinolones have moderate antimicrobial activity against A baumannii. Although levofloxacin has been shown to yield a lower MIC compared with ciprofloxacin and ofloxacin against Acinetobacter spp., overall resistance rates to ciprofloxacin and levofloxacin in clinical isolates are around 50% [135]. Nonetheless, the activity of fluoroquinolones against recent multidrug-resistant or imipenem-resistant isolates has been reported to be low [36,133]. The clinical data are based on in vitro studies where levofloxacin showed effectiveness similar to imipenem in a mouse pneumonia model against a strain susceptible to both agents [135]. However, no comprehensive evidence exists for the effectiveness of fluoroquinolones in the treatment of human infections caused by A baumannii.

59.6.7 Combination Therapy

Several novel antibiotic combinations demonstrated increased activity in vitro compared with that of any single agent against multidrug-resistant A. baumannii isolates. Whether these combinations yield improved outcomes over those seen with a polymyxin or another agent alone remains to be determined. However, against infections with species resistant to all antibiotics, including polymyxins, novel combinations are the only remaining therapeutic option. Several drug combinations have been tested, mostly involving colisitin, carbapenems, rifampicin, fluoroquinolones and sulbactam [136].

Although most of the studies were done in vitro and in animal models of pneumonia, they show that combined therapy, especially the combination with rifampin, obtained better results than monotherapy with carbapenems or colistin [137-141]. The colistin and rifampicin combination (colistin sulphomethate sodium (2 million IU 3 times a day and intravenous rifampicin 10 mg/kg every 12 h) in the treatment of ventilator-associated pneumonia or bacteraemia caused by carbapenem-resistant A. baumannii demonstrated a clinical response of 76% and mortality of 21% [139].

The combination of imipenem and ripampicin has been investigated in some clinical studies; however, the published data are contradictory. Although the combination is synergistic, in vitro studies indicate that because 70% of patients develop high rates of resistance to rifampicin, this combination cannot be recommended [142]. The combination of imipenem with sulbactam has demonstrated synergistic activity in vitro, although some work indicates that the association of carbapenem with ampicillin-sulbactam is associated with better outcomes than the combination of imipenem with amikacin or carbapenems alone. The clinical utility of this combination in patients infected with carbapenem-resistant A. baumannii is not well established [91,143].

The assessment of in-vitro synergy of the combination of imipenem with a polymyxin against carbapenem-resistant A baumannii strains has provided mixed findings. Among other polymyxin-based combination regimens for multidrug-resistant A baumannii, the combination of colistin with a carbapenem has shown in vitro either synergistic or indifferent activity [144,146] but clinical effectiveness has not been substantiated [145]. Tigecycline has demonstrated synergy with levofloxacin, amikacin, imipenem and colistin, but there are few data at present to recommend its systematic use [147].

59.7 Specific Infections Due to A. Baumannii in Neurosurgery Intensive Care Units

Acinetobacter baumannii is an important cause of nosocomial infections. Risk factors specific for nosocomial infection include length of hospital stay, surgery, wounds, severity of underlying diseases, previous infection, faecal colonization with Acinetobacter, treatment with broad-spectrum antibiotics, especially amikacin and imipenem, parenteral nutrition, indwelling central intravenous or urinary catheters or other invasive procedures, admission to a burn unit or ICU, and mechanical ventilation or tracheostomy [28,148].

In many cases, these infections have significant morbidity and mortality. Some studies report an overall mortality rate of 43.3%, a related mortality of 30%, and attributable mortality of 24.3%, with a worse prognosis for critical ICU patients infected by this bacterium compared to those infected by other microorganisms [149].

59.7.1 Postsurgery Nosocomial Meningitis. General Characteristics

A. baumannii meningitis is an infrequent infection mostly associated with intraventricular catheters, cerebrospinal fluid (CSF) fistula or head trauma [148,149]. It is a serious problem in the neurosurgical ICU, especially in patients with intraventricular catheters where the incidence of infection varies from 0 to 27% [150-152].

The risk of nosocomial meningitis in these patients is related to [155-157]:

• Type of neurosurgical procedure.
  
• Glasgow Coma Scale <10.
  
• Emergency surgical procedure.
  
• Presence of surgical wound infection.
  
• Presence of an external CSF drain.
  
• Duration of an intraventricular catheter >5 days.
  
• Absence of antibiotic prophylaxis.

The average incidence is around 2.3% (0.5-11%) and varies with the type of intervention [156]:

• Clean 0.8-5%.
  
• Clean with insertion of foreign material 6.9%.
  
• Clean-contaminated 6.8%.
  
• Contaminated 9.7%.
  
• Dirty-infected 9.1%.

The most frequent mode of acquisition of nosocomial meningitis is direct transmission during invasive neurosurgical procedures (80%). The extension from a contiguous focus (otitis, mastoiditis, sinusitis, subdural empyema and epidural abscess) and cases secondary to bacteraemia from a distant focus only account for 20% of nosocomial bacterial meningitis [156]. Some studies indicate that up to 40% of patients harbour colonization or infection by the microorganism in places other than the central nervous system (CNS) before the onset of meningitis [153]. Given that the main route of acquiring meningitis is through surgical wounds or intraventricular catheters, this situation is of great importance. Hence, these patients should be monitored systematically for colonizing flora and measures of asepsis applied in their care.

The clinical manifestations of postsurgical meningitis caused by A. baumannii are unremarkable, mostly fever and progressive loss of consciousness. Therefore, these manifestations are attributed to the underlying disease, subsequently delaying the final diagnosis of meningeal infection, and representing a prognostic factor of mortality [105,157]. CSF data are consistent with an increased leukocyte count (75-100% polymorphonuclear leukocytes) accompanied by elevated protein with normal or decreased blood glucose levels. Due to the poor specificity of clinical and laboratory data, routine Gram staining and culture are essential in patients with fever of unknown origin and intraventricular catheter.

Infection of CSF shunts carries high morbidity and, above all, taken together, high mortality, which has been estimated to be 15-20%, which may even be higher in certain risk groups, such as preterm infants. The average incidence is 2.6% (range, 4.5-14%) [157,158]. CSF shunts can be divided into two groups: internal referrals or referral shunts and external ventricular drain or external lumbar drain.

• The most commonly used internal shunts are ventriculoperitoneal devices which drain into the abdominal cavity. Ventriculoatrial shunts are used less frequently and tend to be placed in patients in whom the abdominal route is not feasible. The incidence of infection in CSF internal shunts is between 1.5 and 39% (mean, 10%) according to the series. The most important factor associated with infection is the technical expertise of the neurosurgeon. Arguably, following the largest series, overall infection rates >10-15% are hardly admissible and demand the implementation of preventive strategies. The organisms involved are usually skin flora. Coagulase-negative Staphylococci (mainly S. epidermidis) are the most common pathogens, followed by S. aureus
  
• External shunts are catheters that communicate the subarachnoid or ventricular space with the outside. The main therapeutic indications are: acute hydrocephalus, massive intraventricular hemorrhage, intracranial pressure measurement, closure of CSF leaks, and occasionally drug administration. The incidence of infection differs depending on the device: in the case of an external shunt or peripherally inserted central catheter (PICC) it ranges from 5 to 7% and 3-5% for the Ommaya reservoir. In this case, the causal organisms are almost always, Staphylococci and Gram-negative pathogens. Patients with this type of drainage are frequently admitted to ICUs where the prevalence of nosocomial infection, especially from often multiresistant gram-negative bacilli, is high. Infection rarely occurs at the time of catheter insertion, but rather over subsequent days. External catheters remaining in place beyond 5-7 days are at highest risk.

Several risk factors associated with infection of internal shunts are: duration of surgery, vascular thrombosis, age, resurgery, ventriculoatrial > ventriculoperitoneal.

Risk factors associated with infection of external lines are shown in Table 59.1.

Table 59.1. Risk factors associated with external shunts.

The most common clinic manifestation [155,156] is shunt malfunction syndrome, consisting of headache, nausea or vomiting, behavioural changes or gradual decrease in level of consciousness, with or without fever. These symptoms are attributable to intracranial hypertension and are suspicious of infection.

In peritoneal shunts, abdominal clinic is common (up to 40% of cases), often presenting as pain in the right lower quadrant, with or without signs of peritoneal irritation. Other complications include intestinal perforation or pseudo-obstruction symptoms. Any abdominal symptoms in a patient with a peritoneal shunt should suggest the possibility of infection. Abdominal ultrasound may reveal a cystic image or inflammatory liquid mass in the distal insertion of the catheter.

Table 59.2. Diagnostic criteria for external shunt infection.

Ventriculoatrial shunt infection manifests mainly with fever, which can be elevated and accompanied by chills and even sepsis. Potential complications are severe, such as tricuspid endocarditis, septic pulmonary embolism, paradoxical cerebral embolism, mycotic aneurysm in the territory of the pulmonary artery, cardiac tamponade, myocardial perforation, pseudotumour right atrial thrombosis in situ or diffuse glomerulonephritis associated with hypocomplementemia and nephritic syndromes.

External shunt ventricular catheter infection manifests with the development of ventriculitis, fever and altered mental status. As in shunt infection, meningitis can occur if ventriculitis is severe. Sometimes, there are signs of infection at the catheter insertion point. Occasionally, an abscess may occur in the intracerebral route of the catheter. The infection of external lumbar drainage catheters may lead to predominantly purulent meningitis and spinal cord that, if severe or not treated promptly, will also cause ventriculitis.

Diagnostic criteria for postoperative meningitis secondary to external shunts have been developed [159].

The final diagnosis is based on clinical and CSF cytochemical findings of a microorganism isolated in the CSF culture. If necessary, the catheter is removed (all CSF shunts, internal or external, are removed, whatever the reason, and a culture from the catheter tip is obtained). In external lines, the fluid sample is obtained through a ventricular or lumbar catheter. In an internal line, CSF is usually obtained by puncturing the reservoir or valve, or sometimes through the exteriorized distal catheter. In patients with a permanent ventriculoperitoneal shunt, lumbar puncture is contraindicated, as there is danger of locking, and the CSF sample taken by lumbar puncture may differ biochemically and biologically from that taken from the reservoir (infection site).

CSF samples must be grown in aerobic and anaerobic conditions. In some slow-growing infections, the fluid characteristics may be normal and the cultures negative or take long to grow, so that infection is sometimes determined only when culture of the catheter, once removed, is positive (5-10% cases). Lumbar CSF culture offers maximum sensitivity in lumboperitoneal shunts (80-90%) but decreases significantly in ventriculoperitoneal shunts (50-60%) and even more in ventriculoatrial shunts (40%). Ventricular CSF generally shows an inflammatory response with pleocytosis of variable intensity, but in general an average of 100-150 cells. Glucose may be decreased and protein is usually elevated, although usually mild to moderate. The infection of a derivation can be mildly or asymptomatic and present with normal biochemical CSF characteristics, so that only microbiological study can document its existence. In such cases, the results of Gram staining and density of bacterial growth need to be assessed and doubtful cultures repeated, given that contamination may occasionally occur.

Blood cultures must be obtained if the patient is septic. The positivity of blood cultures is <20% in ventriculoperitoneal shunts but up to 95% in ventriculoatrial shunts. A surgical wound or decubitus skin ulcer in the path of the catheter must also be cultivated if it shows signs of infection. Characteristics of meningitis secondary to CSF leak are different from ventricular shunts [160]. The occurrence of CSF leaks is relatively common after traumatic brain injury and certain types of surgical procedures. The incidence of CSF leaks following head injury varies from 2.6 to 30% depending on the type and location of injury. The cumulative incidence at 10 years of meningitis in untreated CSF leakage ranges from 10 to 30% and mortality can be >10% [160]. The most common causative agent in meningitis associated with CSF fistulas is S. pneumoniae [161,162].

59.7.2 Postneurosurgery Meningitis Caused by A. baumannii

Nosocomial meningitis caused by A. baumannii is a major problem in the ICU, especially in patients with intraventricular catheters where the incidence of infection varies from 0 to 27% depending on the study [150-152]. Meningitis is more common in patients with intraventricular hemorrhage, head trauma, prolonged hospital stay and ICU stay [101,150-153]. Other risk factors are the presence of intraventricular catheters for more than 7 days in all postsurgical meningitis [154], and previous antibiotic therapy.

The incidence of nosocomial meningitis caused by A. baumannii varies across different series. In large series, it ranks as the fifth major cause of nosocomial meningitis and in recent series it is the second leading cause of infection in patients with ventricular shunts in some ICUs [163-165].

Nosocomial meningitis caused by A. baumannii often has a subacute onset with a longer course than community-acquired meningitis [166]. The clinical manifestations of postoperative meningitis caused by A. baumannii are mainly subacute fever and progressive loss of consciousness. In many cases these manifestations are attributed to the underlying disease, thus delaying the final diagnosis of meningeal infection, which is a predictor of mortality [101,153]. A small number of patients may show meningeal signs, neurological or seizure focus; however, since many cases occur in sedated patients under mechanical ventilation these data are difficult to assess. CSF data are consistent with increased leukocyte count in f late diagnosis with a 75-100% polymorphonuclear leukocyte count, accompanied by elevated protein with normal or decreased blood glucose levels. There are reports of contamination, so that in suspicious cases repeated lumbar puncture may be useful [167]. The nonspecific clinical and laboratory data make routine performance of Gram staining and culture essential in patients with fever of unknown origin, intraventricular catheter carriers or those admitted to a neurosurgical ICU.

The published mortality rate is 15-71% and 33% in our own experience [101,153]. In some reviews the patients who died had significantly increased pleocytosis and elevated protein, which would seem a worse prognostic sign although not statistically significant [153]. What is clearly established is that the main determinants of mortality are the absence of foreign material removal and the delay of appropriate treatment. Early intraventricular catheter removal with adequate empirical therapy are essential for the survival of patients.

59.7.3 Agents in the Treatment of Meningitis Caused by A. baumannii

Acinetobacter spp. quickly develop resistance to multiple antimicrobials. This complicates the treatment of these infections, making the search of new agents and the return to old drugs imperative.

Cephalosporins

The current Infectious Diseases Society of America (IDSA) guidelines recommend as empirical treatment of postsurgical meningitis a combination of vancomycin plus cefepime, ceftazidime or meropenem [168]. But current resistance rates of Acinetobacter spp. to both cefepime and ceftazidime are >50% and in some hospitals even approach 100% for strains resistant to carbapenems. These data currently discourage their use as empirical treatment. In the few cases where they may be used, the usual dose should be increased to supply 12 g/day of ceftazidime and 2 g/8 h of cefepime [163].

Carbapenems

Until the emergence of resistance, carbapenems alone or in combination with amikacin were the first-line treatment for this type of infection. However, resistance to the new antibiotics in recent years has led to the use of alternative agents such as ampicillin-sulbactam or colistin [152]. Meropenem is preferred over imipenem given the risk of imipemem-associated convulsions at doses necessary for treating meningitis [84,86,87]. It is sometimes difficult to distinguish drug-induced seizures from those produced by the disease causing meningitis. Given that many of these patients have potentially epileptogenic lesions, it seems recommendable to avoid the use of this drug. Doripenem has some epileptogenic activity in animals, so its use is discouraged in the absence of new data. However, meropenem is associated with a very low risk of seizures even in the presence of meningitis, making it the carbapenem of choice in this infection [169].

Several studies have investigated the most effective meropenem dose in meningitis. The most commonly used dose is 2 g/8 h administered intravenously over 30 minutes and it has been compared against infusion of 2 g/8 h over 3-4 hours. One of the problems of treatment with carbapenems is not only the increasing emergence of resistant strains but also the emergence of resistance during treatment. What the scarce literature data seem to show is that 3-hour infusion is associated with less emergence of resistance during treatment, as this is the currently recommended route in this treatment.

Ampicillin-sulbactam

Sulbactam was introduced in the 1980s as a beta-lactamase inhibitor in combination with beta-lactamic antibiotics [5] with in vitro activity against Acinetobacter spp. enhanced by its affinity for penicillin-binding proteins. Intravenous sulbactam penetrates only 1% of the blood-brain barrier but increases up to 32% in meningeal inflammation [121,172]. The combination of ampicillin-sulbactam has been used in doses of 2 g for 6-8 hours, with a mortality rate of 20-25% [101,121].

In our experience, the mortality was 33% in about 4 cases treated with 3 g/8 h and it was significantly lower than with other treatments, except for a combination of intrathecal and intravenous colistin [101]. In a series of 8 cases published by Jimenez Mejias et al. [121], doses of 1 g/6-8 hours led to the death of patients receiving treatment every 8 hours. A dose of 2 g/6 h is now considered more suitable for the treatment of meningitis [163].

Fluoroquinolone

Quinolones, especially levofloxacin, exhibit in vitro activity against Acinetobacter spp. [173], but problems such as high resistance rates (over 60%), scarce clinical experience, and reduced penetration across the blood-brain barrier limit their role in the treatment of meningitis. Experience in the treatment of A. baumannii meningitis is limited to only four isolated cases but with therapeutic success [174,175]. Quinolones penetrated 6-37% of the blood-brain barrier [176], so that it may be necessary dose to 800 mg/8 h with ciprofloxacin. However, this higher dose in treating meningitis could be accompanied by a theoretical risk of seizure [177].

Current recommendations [163,168] advise quinolones only as an alternative treatment in the absence of other options. The recommended doses are 400 mg/8 h or more with ciprofloxacin and 750 mg/24 h or 500 mg/12 h for levofloxacin.

Aminoglycosides

Bacterial multiresistance and the poor penetration of many drugs across the blood-brain barrier have led to the use of intrathecal therapies initially with aminoglycosides and most recently with colistin. The use of intrathecal and intravenous amikacin has been reported in the treatment of meningitis refractory to standard therapy in a small number of cases with cure rates of 50-60% [171,178]; however, given the low penetration of aminoglycosides in the CSF, it must be administered only by intrathecal route. The exact dose of intrathecal amikacin has not been established and varies between 5 and 50 mg/24 h. The most frequent dose is 30 mg/24 h [163]. In recent study a 20 mg/day dose achieved cure rates of 83.4% without causing side effects [101].

Recent studies on 55 episodes of meningitis caused by A. baumannii found that patients who had received intravenous and intrathecal treatment had better outcomes than those receiving only parenteral treatment, although the small number of cases did not allow for statistically significant differences [101].

Table 59.3. Main clinical studies on A. baumannii meningitis treatment.

Colistin

The role of colistin in the treatment of meningitis was initially limited due to its poor CSF penetration (25% of serum levels) without modifications in the presence of meningeal inflammation [179]. However, it has been administered in isolated clinical cases by intrathecal and intravenous routes with good results [101,180]. It is the first-line treatment in multidrug-resistant A. baumannii strains [184]. Recent series described the cure of 8 cases of nosocomial meningitis at a dose of 225 mg/8 h by the intravenous route. However, the use of high doses of colistin increases the risk of nephrotoxicity [179,180,182]. Due to the suboptimal penetration of colistin through the blood-brain barrier [179], the drug is administered by the intraventricular or intrathecal route [101,111,63,183,184] or in combination with other antibacterial agents such as aminoglycosides [11,16,101,184].The dose of intrathecal colistin is generally 5 mg/12 h. In recent study the dose was 10 mg/12 h without increasing side effects [101]. In this review, all patients treated with intravenous and intrathecal colistin survived without evidence of local toxicity. Although the small number of cases studied limits the statistical significance of the results, the present data show that combined colistin by either route can be both safe and effective for this infection [101]. These findings support evidence that intravenous treatment alone should not be recommended. Recently, some cases have been successfully treated with intrathecal colistin alone, although at present there are few data to support such therapy. Treatment regimens for nosocomial meningitis that don’t include intravenous colistin with intrathecal colistin should be considered suboptimal [101,163].

The duration of treatment is controversial, but it should be continued for at least 3 weeks after the withdrawal of foreign bodies or after two consecutive negative cultures.

Rifampicin

Rifampicin may be useful in combination with various other drugs used in meningitis treatment like colistin, ampicillin-sulbactam or carbapenems. It has in vitro synergy with colistin and its use could be considered as adjuvant treatment. However, intravenous rifampicin alone without other treatment is discouraged.

Tigecycline

New antibiotics include tigecycline, a member of a new class of antibiotics, the glycines. In animal studies of meningitis, tigecycline at a single dose of 20 mg/kg/day showed CSF concentrations >1 μg/ml 3 h after infusion. The CSF penetration of tigecycline is minimal, with concentrations of 0-15 μg/ml at 90 minutes after the administration of a dose of 100 mg far under the required MIC, so its use cannot be recommended [187], although an isolated cases of cure of meningitis with tigecycline have been described [188].

59.7.4 Empiric Treatment of Nosocomial Meningitis Due to A. baumannii

Nosocomial meningitis is an important cause of morbidity and mortality; it requires urgent and effective treatment, including antibiotic therapy and general supportive measures of the critically ill patient. Delay in the diagnosis and inadequate treatment are the most important factors of mortality. For this reason, in the early diagnosis of meningitis it is very important to perform complementary techniques and quickly initiate appropriate antimicrobial therapy to prevent worsening of the patient’s condition.

It is therefore recommended that in patients with suspected meningitis (and before administering antibiotics, except in selected cases as detailed below), blood samples and lumbar puncture (unless contraindicated) should be taken and sent to the microbiology laboratory for culture. If a CT of the head is required prior to lumbar puncture, this should not delay the delivery of treatment, so that blood cultures will be done and the appropriate therapeutic regimen initiated. Once the CT is obtained, if there are no contraindications, a lumbar puncture will be carried out. We recommend Gram staining of the CSF sample in suspected cases of nosocomial meningitis.

The aim of antibiotic treatment should be to achieve rapid sterilization of the CSF. Antibiotics should have rapid bactericidal activity, as bacteriostatic action is not enough to clear the infection and delayed sterilization of CSF has been associated with an increased incidence of neurological sequelae. It is essential that the antibiotic concentration in the CSF is greater than the minimum bactericidal concentration (MBC), and that the ratio between both concentrations (the bactericidal index) exceeds 1. Bactericidal activity in the CSF is optimal if the bactericidal rate is about 10. When the antibiotic does not reach the necessary concentration in the CSF through systemic administration, direct administration by the intraventricular or intrathecal route is necessary. The initial antibiotic dose must be maintained throughout the entire course of therapy without reducing the dose when the patient improves, since the penetration of the antibiotic across the blood-brain barrier normalizes as the CSF decreases. In nosocomial meningitis, empiric therapy should cover P. aeruginosa and A. baumannii and Staphylococcus spp., especially if an intraventricular catheter is present. Empirical treatment for nosocomial meningitis due to A. baumannii is illustrated in Table 59.4.

Kind of risk

Therapy

If risk factors of Acinetobacter spp. infection:   Only gold members can continue reading. Log In or Register to continue Share this: Click to share on Twitter (Opens in new window) Click to share on Facebook (Opens in new window) Related Related posts: Neuroscience Critical Care: Two Experts’ Point of View Neurocritical Care of Patients With Arteriovenous Malformations Monitoring Cerebral Blood Flow and Cerebral Autoregulation: Basic Principles, Techniques, Common Patterns and Interpretation of Results Endocrinology of Acute Brain Injury Monitoring Brain Chemistry by Microdialysis During Neurointensive Care Acute Paraplegias and Quadriplegias of Non-traumatic Cause Stay updated, free articles. Join our Telegram channel Join Tags: Intensive Care in Neurology Jan 2, 2017 | Posted by admin in NEUROLOGY | Comments Off on Acinetobacter Infections: An Emerging Problem in the Neurosurgical Intensive Care Unit Full access? Get Clinical Tree Get Clinical Tree app for offline access Get Clinical Tree app for offline access