Gram-negative Bacillary Meningitis Research Articles

Cefotaxime therapy of neonatal gram-negative bacillary meningitis.

Seven neonates were treated with cefotaxime during eight episodes of Gram-negative bacillary meningitis and sepsis. The causative organisms were Escherichia coli in six cases and Klebsiella pneumoniae and Enterobacter sakazakii in one each. After identification of the pathogen cefotaxime was used alone in six instances. Two patients with brain abscesses received adjunctive therapy with another antibiotic. The sterility of cerebrospinal fluid was documented after a mean of 3.3 days of therapy. Mean cerebrospinal fluid bactericidal titer was 1:64. All patients recovered with good neurologic outcome. Cefotaxime in a dosage of 150 mg/kg/day divided every 6 hours intravenously seems safe and effective therapy for neonatal Gram-negative bacillary meningitis.

Review of Pseudomonas aeruginosa meningitis with special emphasis on treatment with ceftazidime.

Pseudomonas aeruginosa meningitis is a rare disease and the optimal antibiotic therapy for this condition is not well established. Results of therapy using various regimens reported since 1960 are reviewed. Ceftazidime, an investigational cephalosporin with potent antipseudomonal activity, has been used to treat P. aeruginosa meningitis in Europe and North America. The results in 24 patients are analyzed here. Most patients had failed to respond to other regimens before commencing therapy with ceftazidime. Nineteen (79.2%) of these patients were cured, and only three (12.5%) were considered therapeutic failures. Hence, ceftazidime is a useful agent in the treatment of gram-negative bacillary meningitis and may be superior to other cephalosporins on the market for the treatment of pseudomonas meningitis. Since development of resistance is a concern, however, it may be prudent to use a concomitant parenteral aminoglycoside with ceftazidime for the first week in the treatment of P. aeruginosa meningitis.

Bacterial Meningitis in the Elderly-Reply

—Dr Harris focuses on specific clinical characteristics of our older adult population (age, ≥50 years) and reiterates concerns regarding efficacy of third-generation cephalosporins in the treatment of gramnegative bacillary meningitis. 1 It is important to differentiate those patients with microbiologically proved bacterial meningitis from those with presumed bacterial infections treated as such. In the latter group, situations associated with a negative bacterial culture included prior antibiotic treatment, parameningeal focus of infection, and CSF leak due to prior trauma or neurosurgical procedure. While higher mortality correlated with positive microbiologie diagnosis in our series of patients,1 characteristics (eg, preexisting neurologic disease, previous neurologic surgical procedures, change in sensorium at time of presentation, and community onset vs hospital onset) did not differ significantly between these two subgroups (Table 1). The eight patients with aseptic meningitis had no preexisting neurologic disease or neurologic surgical procedures, and all had community-acquired infection. The mean CSF white blood cell

Gram-negative Bacillary Meningitis

The incidence of gram-negative bacillary meningitis has increased significantly in the past two decades. Approximately two thirds of all reported cases have occurred after neurosurgical procedures. With the development of the newer cephalosporins, the overall mortality rate has decreased from 40 to 80 per cent to 10 to 20 per cent.

A Study of the Penetration of Temocillin in the Cerebrospinal Fluid1

Temocillin concentrations in serum and cerebrospinal fluid (CSF) samples from 8 patients were assayed by high pressure liquid chromatography. It was possible to determine sequential series of ventricular (CSF) and serum concentrations in 4 adult neurosurgical patients with slight to moderate impairment of blood-CSF barriers, because serial CSF samples were obtained from external ventricular drains. In 4 other patients with meningitis, temocillin was given in addition to the regular treatment schedule and 6 'spot' concentrations of temocillin in lumbar CSF and serum samples were determined. Temocillin CSF concentrations in these subjects seemed to be inadequate for the treatment of Gram-positive bacterial meningitis and only partially valuable for the treatment of Gram-negative bacillary meningitis.

Effectiveness of Cefotaxime in Gram-negative Meningitis

We treated 12 adult patients who had gram-negative bacillary meningitis with cefotaxime administered intravenously at a dose of 2 g every 4 hours. The etiological organisms included Haemophilus influenzae (3 cases), Serratia marcescens (3 cases), Klebsiella pneumoniae (3 cases), Escherichia coli (2 cases), and Enterobacter (1 case). The infection followed a neurosurgical procedure in 6 cases. The mean inhibitory and bactericidal concentrations of cefotaxime for the isolates ranged from 0.125 to 0.25 microgram/ml. The cerebrospinal fluid (CSF) concentrations of cefotaxime ranged from 5.0 to 15.2 micrograms/ml, and the CSF bactericidal titers were 1:64 to 1:128. The CSF in all patients was sterilized within 96 hours. All 12 patients recovered, and there were no relapses.

Piperacillin A Review of its Antibacterial Activity, Pharmacokinetic Properties and Therapeutic Use

Piperacillin is one of the new generation of semisynthetic penicillins which can be administered intravenously or intramuscularly. It has a broad spectrum of activity against Gram-positive and Gram-negative aerobic and anaerobic bacteria. Although piperacillin has shown greater activity against beta-lactamase-producing organisms than the other penicillins, it is hydrolysed by the plasmid-mediated beta-lactamases (TEM-1). Activity against Pseudomonas aeruginosa is better than that of ticarcillin, carbenicillin and mezlocillin. Although only limited controlled studies have been reported, in those which have been conducted and in a larger number of open studies piperacillin was effective in the treatment of complicated urinary tract infections and lower respiratory tract infections, particularly pneumonia, caused by Gram-negative bacilli. Favourable clinical results have been obtained in patients with infections caused by mixed aerobic/anaerobic organisms (such as intra-abdominal infections) but the relatively average in vitro activity of piperacillin against Bacteroides fragilis may not indicate its usage in situations where this organism is the suspected or proven pathogen. Piperacillin in combination with an aminoglycoside or a 'third generation' cephalosporin gave encouraging results in the treatment of infections in immunocompromised patients, whilst its penetration into the diseased central nervous system and lack of toxicity indicate a potential value in the treatment of neonatal Gram-negative bacillary meningitis, particularly where the causative organism is Pseudomonas aeruginosa. Whether piperacillin alone is appropriate therapy for conditions usually treated with aminoglycosides (other than pseudomonal infections) needs additional clarification, but if established as equally effective in such conditions it has the advantages of its apparent lack of serious adverse effects and freedom from the need to undertake plasma concentration monitoring. These advantages would not, however, apply when considering one of the new (third generation) cephalosporins as alternative therapy in non-pseudomonal infections. Generally, however, it is still considered necessary to treat serious and complicated infections with combination therapy, either a cephalosporin, or in cases of resistance to P. aeruginosa an aminoglycoside.

Penetration of aztreonam into cerebrospinal fluid of patients with and without inflamed meninges.

Aztreonam was administered as a single, 2-g intravenous dose to 25 patients with noninflamed meninges and to 9 patients with inflamed meninges. It was well tolerated and was detected in the cerebrospinal fluid at the initial sampling period at 1 h after the end of infusion. Aztreonam levels in the cerebrospinal fluid of patients with inflamed meninges were four times higher than those recorded for the same time period in patients with noninflamed meninges. Aztreonam concentrations in cerebrospinal fluid in the presence of normal and inflamed meninges exceeded the inhibitory and bactericidal concentrations for most gram-negative bacteria. Thus, a multiple-dose treatment regimen with 2-g intravenous doses every 6 h appears to be appropriate for clinical trials of aztreonam for the treatment of gram-negative bacillary meningitis which is caused by susceptible organisms.

Cephalosporin antibiotic agents.

The cephalosporins are a group of antibiotic agents that have been available now for 20 years. Three classes, or generations, of cephalosporins are recognized. The newer third-generation drugs have wider spectra of antibacterial activity; because of this attribute and their ability to achieve high bactericidal titres in CSF these newer compounds constitute an advance in antibiotic therapy by providing safe and effective treatment for Gram-negative bacillary meningitis. The earlier cephalosporins provide cheap, useful and convenient prophylaxis for vascular and orthopaedic operations near the inguinal area. Comparative trials with other broad-spectrum agents need to be performed before the true place of the third-generation agents in anti-infective therapy and prophylaxis is finally determined.

Third-generation cephalosporins: A critical evaluation

Six third-generation cephalosporins--cefotaxime, moxalactam, cefoperazone, ceftizoxime, ceftriaxone, and cefmenoxime--are reviewed; covered are chemistry and structure-activity relationships, mechanism of action, spectra of activity, pharmacokinetics, clinical utility, adverse effects, and cost effectiveness. The third-generation cephalosporins have a similar mechanism of action to that of other beta-lactam antibiotics. None of the agents is particularly active against certain gram-positive bacteria, including methicillin-resistant Staphylococcus aureus; the drugs are effective against gonococci, Haemophilus influenzae, and Neisseria meningitidis. Several common gram-negative pathogens are susceptible to the third-generation cephalosporins, including Escherichia coli, Klebsiella, Citrobacter diversus, Proteus, and Morganella. About 50% of Pseudomonas aeruginosa isolates are susceptible. Only moxalactam has good activity against Bacteriodes fragilis. The pharmacokinetic profiles of the six agents reveal some important differences. The half-life of ceftriaxone allows once-daily dosing in many patients; the half-lives of ceftizoxime and cefoperazone permit dosing every 8-12 hours. Cefoperazone and ceftriaxone are highly protein bound, but the clinical relevance of this is unknown. Generally, the agents penetrate most body tissues and fluids well. Moxalactam and cefotaxime and possibly ceftriaxone effectively penetrate into the cerebrospinal fluid well. The third-generation cephalosporins have become the accepted drugs of choice for the treatment of adult gram-negative bacillary meningitis; as more experience is gained, they are likely to become the drugs of first choice for neonatal (with ampicillin) and childhood (except for moxalactam) meningitis. Serious infections of Enterobacteriaceae can be treated with these agents, thereby avoiding use of the aminoglycosides. Moxalactam is comparable with combination therapy in treating intra-abdominal infections. Adverse effects associated with use of the third-generation cephalosporins are generally similar to those that occur with other beta-lactam antibiotics with the exception of coagulopathies and the disulfiram reaction seen with moxalactam and cefoperazone. Despite the relatively high cost of the third-generation cephalosporins, they are often cost effective because of their reduced dosing frequencies, broad spectra of activity, and effectiveness in serious infections for which more toxic antibiotics have been required in the past.

Trimethoprim-sulfamethoxazole for bacterial meningitis.

Trimethoprim-sulfamethoxazole has excellent microbiologic activity against most pathogens that produce meningitis; both components of this drug have high penetration into tissues, including the cerebrospinal fluid. Clinical experience shows that trimethoprim-sulfamethoxazole may be beneficial in the treatment of gram-negative bacillary meningitis caused by organisms only moderately susceptible to third-generation cephalosporins (Enterobacter cloacae, Serratia marcescens) or resistant to these antibiotic agents (Pseudomonas cepacia, Acinetobacter). The success of trimethoprim-sulfamethoxazole in the treatment of four patients with Staphylococcus aureus and two patients with Listeria monocytogenes meningitis shows that this drug may also be useful in treating infrequent types of gram-positive meningitis.

Prospective Evaluation of Moxalactam Therapy for Gram-Negative Bacillary Meningitis

In a prospective evaluation twenty patients with gram-negative bacillary meningitis were treated with moxalactam, either alone or in conjunction with other antibiotics. Of thirteen patients who received only moxalactam, eight recovered, one failed to respond, and five died of causes other than meningitis. Cultures of CSF were negative before death in each instance. Thirteen (65%) of 20 treated patients recovered. Reversible hypoprothrombinemia and bleeding occurred secondary to moxalactam therapy in one patient. The mortality from gram-negative bacillary meningitis remains high owing to the incidence of associated underlying disease. Moxalactam brings about bacteriologic control in a large proportion of patients who are infected with highly sensitive gram-negative enteric bacilli.

Antagonism by chloramphenicol of broad-spectrum beta-lactam antibiotics against Klebsiella pneumoniae.

Chloramphenicol combined with cefotaxime, moxalactam, cefoperazone, aztreonam, or imipenem was tested in vitro against clinical isolates of Klebsiella pneumoniae. By time-kill cultures (killing curves), chloramphenicol interfered with activity of all five beta-lactams. When chloramphenicol was added before the beta-lactams, the action of cefotaxime, moxalactam, or cefoperazone against all isolates was antagonized at all times tested. The action of aztreonam was antagonized against four of six isolates. With imipenem, antagonism occurred against half of the isolates at some time during 24 h when chloramphenicol was added simultaneously, provided that a sufficient inoculum of K. pneumoniae was employed. Generally, less antagonism resulted when chloramphenicol was added after the cephalosporins. Interference of bactericidal activity of three new cephalosporins by chloramphenicol has potential clinical relevance to the therapy of gram-negative bacillary meningitis. The lesser antagonism of aztreonam and imipenem by chloramphenicol is of uncertain clinical relevance but indicates that this in vitro phenomenon may apply to a wide range of beta-lactam antibiotics.

<italic>Staphylococcus aureus</italic> Meningitis

Thirty-eight cases of meningitis caused by Staphylococcus aureus, occurring from 1966 to 1981 at six hospitals associated with the University of Toronto Faculty of medicine, were reviewed. Thirteen patients were children and 25 were adults. Patients were categorised into three groups: Group A (16)--meningitis related to neurosurgery, trauma or cerebrospinal defects; Group B (7)--meningitis occurring with indwelling ventricular shunts; and Group C (15)--spontaneously occurring meningitis. Bacterial endocarditis was associated with one-third of the spontaneously occurring meningitis cases and this group in general ran a more fulminant course. Meningitis related to a ventricular shunt exhibited a more insidious onset with a lower case-fatality rate, similar to the experience with Gram-negative bacillary meningitis. Gram stain of the cerebrospinal fluid was positive in only one-third of cases. Treatment with cloxacillin, administered parenterally, achieved results similar to those with methicillin, while chloramphenicol was associated with a high failure rate.

Diffusion of metioprim, tetroxoprim and sulphadiazine in the cerebrospinal fluid of dogs with healthy meninges and dogs with experimental meningitis.

The diffusion of metioprim (MTP), tetroxoprim (TXP) and sulphadiazine (SDZ) in cerebrospinal fluid (CSF), following single intravenous doses and continuous infusions, was studied in dogs. The drugs penetrated well into the CSF of animals with and without experimental Staphylococcus aureus meningitis. In dogs with healthy meninges, the CSF bioavailability - expressed as the ratio of CSF/plasma area under the curve 0-5-hour values - following continuous infusion was determined to be 86.7% for MTP, 58.2% for TXP and 38.8% for SDZ. In infected animals, CSF availability following continuous infusion increases slightly to ratios of 96% (MTP), 70% (TXP) and 50% (SDZ). For all drugs, the concentrations reached in CSF were above the minimum inhibition concentrations for the majority of Enterobacteriaceae, indicating their potential value in treatment of gram-negative bacillary meningitis.

Gram-negative bacillary meningitis in neurosurgical patients.

The authors report 34 cases of Gram-negative bacillary meningitis related to traumatic cranial lesions or neurosurgery observed between 1973 and 1980 at two neurosurgical units (Institut J. Bordet, Brussels, and Inselspital, Bern). As a typical nosocomial infection, meningitis developed after prolonged hospitalization in most patients, and was mainly due to highly resistant organisms, such as P. aeruginosa and Klebsiella sp. At least 65% of the patients were colonized with the pathogen responsible for the meningitis before the onset of the infection. Ventriculitis, including four cases of ventricular empyema, complicated meningitis in all the 17 patients in whom a ventricular tap was performed. The results of treatment were unsatisfactory. Fifty percent of the patients were cured of their infection, but only 30% survived; 15% of the patients died within 48 hours following diagnosis. The optimum treatment of postsurgical Gram-negative meningitis remains in doubt. The choice of initial antibiotics should take into account the sensitivity patterns of colonizing microorganisms. Chloramphenicol is ineffective against most pathogens commonly involved in this infection. Intrathecal aminoglycosides may fail in the presence of ventriculitis. Intraventricular aminoglycosides are probably justified in critically ill patients. The role of the newer cephalosporins and of co-trimoxazole remains to be defined.

Moxalactam (latamoxef). A review of its antibacterial activity, pharmacokinetic properties and therapeutic use.

Moxalactam (latamoxef) is a new synthetic oxa-beta-lactam antibiotic administered intravenously or intramuscularly. It has a broad spectrum of activity against Gram-positive and Gram-negative aerobic and anaerobic bacteria, is particularly active against Enterobacteriaceae and is resistant to hydrolysis by beta-lactamases. Moxalactam has moderate activity against Pseudomonas aeruginosa, but on the basis of present evidence can not be recommended as sole antibiotic treatment of known or suspected pseudomonal infections. Like the related compounds, the cephalosporins, moxalactam is effective in the treatment of complicated urinary tract infections and lower respiratory tract infections caused by Gram-negative bacilli. As moxalactam is also active against Bacteroides fragilis it has considerable potential in the treatment of intra-abdominal infections in patients with normal immunological mechanisms, as well as in immunocompromised patients, when used alone or in combination with other antibiotics. Likewise, its ready penetration into the diseased central nervous system, its high level of activity against Gram-negative bacilli, and the lack of necessity to monitor drug plasma concentrations, indicate its potential value in the treatment of neonatal Gram-negative bacillary meningitis. Further clinical experience is needed before it can be determined whether moxalactam alone can be used in the treatment of conditions for which the aminoglycosides are drugs of choice, but if established as equally effective, moxalactam has the advantage of being devoid of nephrotoxicity. Bleeding is a potentially serious problem, however, particularly in the elderly, malnourished and in the presence of renal impairment.

Cefotaxime Levels in Ventricular Cerebrospinal Fluid, Determined by Bioassay and by High-Performance Liquid Chromatography

Five series of cerebrospinal fluid (CSF) samples, obtained from external ventricular drains (EVD) of 4 neurosurgical patients with cefotaxime treatment were tested simultaneously by high-performance liquid chromatography (HPLC) and microbioassay using E. coli V 6311/65 as test organism. Higher cefotaxime (CTX) concentrations in CSF were measured by the microbioassay method in 4 of the 5 series, reflecting the microbioassay being influenced by increasing amounts of desacetyl-cefotaxime (DAC) during the post-application interval. Decrease of CTX levels in CSF was consistently faster in tests performed by HPLC than those using microbioassay. The clinical efficacy in gram-negative bacillary meningitis is to be explained by levels of the parent compound CTX in CSF which are several times higher than the minimal inhibitory concentrations (MICs) of most enterobacteriaceae.

Efficacy of trimethoprim/sulfamethoxazole in experimental Escherichia coli bacteremia and meningitis.

We evaluated the activity of trimethoprim/sulfamethoxazole (TMP/SMZ) against a K1 Escherichia coli strain. Minimal inhibitory and bactericidal concentrations were 0.06/1.14 and 0.25/4.75 micrograms/ml, respectively. In vivo studies using an infant rat model of bacteremia and meningitis revealed that TMP/SMZ penetrated well into the cerebrospinal fluid (CSF) and that 37% of serum levels were achieved. The efficacy of TMP/SMZ was compared with that of ampicillin, chloramphenicol, cefotaxime and lamoxactam. Bacterial clearance from blood and CSF was significantly greater with TMP/SMZ than with ampicillin or chloramphenicol and mortality was significantly less than with chloramphenicol (p less than 0.01). However, 3 of 21 (14%) and 2 of 8 animals (25%) still had positive blood and CSF cultures after 3 days of treatment with TMP/SMZ. None of the survivors in the cefotaxime and lamoxactam groups were bacteremic after 1 day of therapy. Furthermore, 5 of 13 animals (38%) treated with TMP/SMZ developed meningitis during therapy, in contrast with none in the cefotaxime and lamoxactam groups. These findings indicate that although the activity of TMP/SMZ is bactericidal in vitro and in vivo against E. coli, TMP/SMZ may not provide optimal therapy for gram-negative bacillary meningitis in this model.

Moxalactam therapy for gram-negative bacillary meningitis.

Twenty patients with gram-negative bacillary meningitis (19 episodes caused by enteric bacilli and one by Pseudomonas aeruginosa) were treated with moxalactam given intravenously. Seventeen patients responded well clinically and bacteriologically without known relapse. Fourteen of 18 isolates from cerebrospinal fluid were susceptible to less than or equal to 0.5 micrograms of moxalactam/ml. Cerebrospinal fluid concentrations of moxalactam in four patients were 2.4-16 micrograms/ml. This accumulated experience indicates that moxalactam has been effective in the treatment of patients with meningitis due to highly susceptible enteric gram-negative bacilli. However, it cannot be recommended as single-drug therapy for meningitis due to P. aeruginosa or Acinetobacter.