Listeria monocytogenes meningoencephalitis in adults: analysis of factors related to unfavourable outcome.

PURPOSE: To analyse the short-term outcome in patients with Listeria monocytogenes meningoencephalitis (LMME) to improve management and outcome. METHODS: Observational study with adult patients with LMME between 1977 and 2009 at a tertiary hospital in Barcelona, Spain. Parameters that predicted outcome were assessed with univariate and logistic regression analysis. RESULTS: Of 59 cases of LMME, 28 occurred in the last decade. Since 1987, a new protocol has been used and 29/45 patients (64%) treated since then received adjuvant dexamethasone. In patients who received this treatment there was a trend towards fewer neurological sequelae (5 vs 33%; p = 0.052). Antiseizure prophylaxis with phenytoin was administered in 13/45 (28%) patients. Seizures occurred in 7/45 (16%) patients, all in the group who did not receive phenytoin. Hydrocephalus presented in 8/59 (14%). It was never present at admission and five patients needed neurosurgical procedures. Sequelae after 3 months were present in 8/45 (18%), mostly cranial nerve palsy. Rhombencephalitis (RE) was related to the presence of neurologic sequelae (OR: 20.4, 95% CI: 1.76-236). Overall mortality was 14/59 (24%), 9/59 (15%) due to neurological causes related to hydrocephalus or seizures. Mortality was defined as early in 36% and late in 64%. In the multivariate analysis, independent risk factors for mortality were presence of hydrocephalus (OR: 17.8, 95% CI: 2.753-114) and inappropriate empirical antibiotic therapy (OR: 6.5, 95% CI: 1.201-35). CONCLUSIONS: Outcome of LMME may be improved by appropriate empirical antibiotic therapy, suspicion and careful management of hydrocephalus. Use of adjuvant dexamethasone or phenytoin in a subgroup of these patients might have a benefit.

Arthritis related to systemic meningococcal disease: 34 years' experience.

The purpose of this investigation was to assess the clinical characteristics, therapeutic aspects, and outcome of arthritis related to invasive meningococcal disease (IMD). All episodes of bacterial meningitis and IMD are recorded systematically. We selected all episodes of IMD, with or without meningitis, that presented arthritis. From 1977 to 2010, 522 episodes of IMD were treated. Thirty-nine of these (7.5 %, 26 women, mean age 33 years) presented arthritis. Of these 39, 37 (95 %) presented skin lesions and 31 (79 %) had meningitis. Twenty (51 %) had positive blood cultures and six (15 %) had shock. No differences were found in skin lesions, shock, or bacteremia compared to cases without arthritis. In contrast to other septic forms, arthritis related to IMD was cured with short antibiotic therapy and without surgical drainage. There was no mortality. All patients recovered and none presented joint sequelae; however, 13 adult patients (33 %) required long-term treatment with steroids due to persistent symptoms. Arthritis related to IMD most frequently affects the knees and ankles, and may be a cause of fever relapse. Short antibiotic therapy is enough in all cases and surgical drainage is not needed. In some adult patients, especially those over 50 years of age, evolution is torpid and steroid therapy may be required in order to achieve recovery.

Evaluation of meropenem alone and combined with rifampin in the guinea pig model of pneumococcal meningitis.

Meropenem is a broad-spectrum carbapenem antibiotic that is highly active against the pathogens causing meningitis. The aims of this study was to determine the efficacies of meropenem alone and combined with rifampin against two Streptococcus pneumoniae strains with different susceptibility to beta-lactams using the guinea pig meningitis model and compare them with the standard ceftriaxone plus vancomycin therapy. All treatments except rifampin were bactericidal from 6 h. The addition of rifampin did not improve the activity of meropenem alone. Our results provide good evidence of the efficacy of meropenem in the treatment of penicillin- and cephalosporin-susceptible and -resistant pneumococcal meningitis similar to that of ceftriaxone plus vancomycin, suggesting that meropenem might be a good option in the management of this infection.

Community-acquired bacterial meningitis in cirrhotic patients.

The Hospital Universitari de Bellvitge (Barcelona, Spain) records all cases of bacterial meningitis in a 120-variable database. The characteristics of bacterial meningitis in cirrhotic patients are not well-known, and all cases of community-acquired bacterial meningitis occurring in cirrhotic patients were therefore identified. During 1977-2002, there were 602 episodes of community-acquired bacterial meningitis in adults, of which 29 (4.8%) occurred in cirrhotic patients. Compared to non-cirrhotic patients, there were significant differences in: duration of disease for >4 days at the time of diagnosis; absence of nuchal rigidity; certain aetiologies, e.g., Escherichia coli and Listeria monocytogenes; renal and liver function impairment; relapse of fever; and incidence of relapse and mortality. Overall, bacterial meningitis in cirrhotic patients was associated with a high mortality rate and a large number of complications. A high index of suspicion is necessary because of the frequent absence of meningeal signs. In addition to the classic meningeal pathogens, other aetiologies, including E. coli and L. monocytogenes, should be considered when prescribing empirical therapy.

Four days of penicillin therapy for meningococcal meningitis.

Fifty consecutive patients with meningococcal meningitis aged 7 to 75 years (mean, 29 years) were treated with intravenous penicillin G sodium (2 to 3 X 10(5) U/kg/d) for four days. Two of the patients (both teenagers) died of fulminant infection during the first 36 hours of therapy and one elderly woman developed aspiration pneumonia requiring penicillin therapy to be prolonged beyond four days. The remaining 47 patients recovered from the infection. On the fourth day, fever, mild meningeal signs, and moderate elevations of cerebrospinal fluid cell counts and protein contents persisted in some patients; nevertheless, all patients were cured without relapse. The results of our study suggest that meningococcal meningitis may be successfully treated with a four-day course of intravenous penicillin G.

Clindamycin vs penicillin for anaerobic lung infections. High rate of penicillin failures associated with penicillin-resistant Bacteroides melaninogenicus.

Thirty-seven adult patients with anaerobic lung infections (27 lung abscesses and 10 necrotizing pneumonias) were submitted to transthoracic needle-aspiration and/or bronchoscopic specimen brush cultures before therapy and thereafter in all cases considered to be failures. Patients were randomly assigned to receive either clindamycin, 600 mg intravenously every 6 hours, or penicillin G, 2 million U every 4 hours for no less than 8 days, until clinical and radiological improvement became apparent. Treatment was continued orally with clindamycin, 300 mg every 6 hours, or penicillin V, 750 mg every 6 hours, until completing a minimum of 4 weeks. Ten of the 47 anaerobes initially isolated from the lung (nine Bacteroides melaninogenicus and one Bacteroides capillosus) were resistant to penicillin, but none were resistant to clindamycin. Five of the nine patients harboring these penicillin-resistant Bacteroides received penicillin, and all failed to respond to therapy. Overall, eight of the 18 patients in the penicillin group and one of 19 in the clindamycin group failed to respond to therapy. These drugs were equally well tolerated in both groups. The presence of penicillin-resistant Bacteroides is a frequent cause of penicillin failure in patients with anaerobic lung infections. In this setting, clindamycin appears to be the current therapy of choice for initial treatment.

Characteristics and antibiotic therapy of adult meningitis due to penicillin-resistant pneumococci.

Of 66 episodes of pneumococcal meningitis seen in Bellvitge Hospital, Barcelona, Spain (January 1981 to June 1987), 15 (23 percent) were due to penicillin-resistant pneumococci [minimal inhibitory concentrations (MICs) of 0.1 to 4 micrograms/ml]. Fifty percent of these strains were also resistant to chloramphenicol. Most were sporadic community-acquired cases. Clinical characteristics were similar in both penicillin-resistant and penicillin-sensitive cases. Those cases with MICs of greater than 1 microgram/ml did not show a response to penicillin therapy. Of nine patients treated with cefotaxime (200 to 350 mg/kg per day) with penicillin G MICs of 0.1 to 4 micrograms/ml and cefotaxime MICs of less than or equal to 0.03 to 1 microgram/ml, seven recovered, one experienced a relapse after 14 days of therapy and the infection was cured with intravenous vancomycin, and one patient died with sterile cerebrospinal fluid. Thus, adults with meningitis due to penicillin-resistant pneumococci may be adequately treated with high doses (around 300 mg/kg per day) of intravenous cefotaxime if MICs of penicillin G are less than or equal to 4 micrograms/ml. Cases with higher resistance may require another antibiotic such as vancomycin.

Impact of antibiotic resistance on chemotherapy for pneumococcal infections.

Over the past three decades, penicillin-resistant pneumococci have emerged worldwide. In addition, penicillin-resistant strains have also decreased susceptibility to other beta-lactams (including cephalosporins) and these strains are often resistant to other antibiotic groups, making the treatment options much more difficult. Nevertheless, the present in vitro definitions of resistance to penicillin and cephalosporins in pneumococci could not be appropriated for all types of pneumococcal infections. Thus, current levels of resistance to penicillin and cephalosporin seem to have little, if any, clinical relevance in nonmeningeal infections (e.g., pneumonia or bacteremia). On the contrary, numerous clinical failures have been reported in patients with pneumococcal meningitis caused by strains with MICs > or = 0.12 microg/ml, and penicillin should never be used in pneumococcal meningitis except when the strain is known to be fully susceptible to this drug. Today, therapy for pneumococcal meningitis should mainly be selected on the basis of susceptibility to cephalosporins, and most patients may currently be treated with high-dose cefotaxime (+/-) vancomycin, depending on the levels of resistance in the patient's geographic area. In this review, we present a practical approach, based on current levels of antibiotic resistance, for treating the most prevalent pneumococcal infections. However, it should be emphasized that the most appropriate antibiotic therapy for infections caused by resistant pneumococci remains controversial, and comparative, randomized studies are urgently needed to clarify the best antibiotic therapy for these infections.

Experimental study of clinafloxacin alone and in combination in the treatment of ciprofloxacin-susceptible and -resistant pneumococcal meningitis.

The increasing incidence of ciprofloxacin resistance in Streptococcus pneumoniae may limit the efficacy of the new quinolones in difficult-to-treat infections such as meningitis. The aim of the present study was to determine the efficacy of clinafloxacin alone and in combination with teicoplanin and rifampin in the therapy of ciprofloxacin-susceptible and ciprofloxacin-resistant pneumococcal meningitis in rabbits. When used against a penicillin-resistant ciprofloxacin-susceptible strain (Clinafloxacin MIC 0.12 microg/ml), clinafloxacin at a dose of 20 mg/kg per day b.i.d. decreased bacterial concentration by -5.10 log cfu/ml at 24 hr. Combinations did not improve activity. The same clinafloxacin schedule against a penicillin- and ciprofloxacin-resistant strain (Clinafloxacin MIC 0.5 microg/ml) was totally ineffective. Our data suggest that a moderate decrease in quinolone susceptibility, as indicated by the detection of any degree of ciprofloxacin resistance, may render these antibiotics unsuitable for the management of pneumococcal meningitis.

Experimental study of meropenem in the therapy of cephalosporin-susceptible and -resistant pneumococcal meningitis.

Meropenem is a carbapenem antibiotic that is highly active against the pathogens causing meningitis. Results with meropenem in the experimental rabbit model of penumococcal meningitis have been controversial, and the possible role of renal dehydropeptidase I in meropenem efficacy has been suggested. The aim of this study was to determine the efficacy of meropenem in two meningitis models and the possible influence of the animal model over results. Two strains of Streptococcus pneumoniae with different susceptibility to beta-lactams have been used in a guinea pig model and the classical rabbit meningitis model. Meropenem was bactericidal at 6 h in the guinea pig model against both strains with a reduction of >4 log ufc/ml. In the rabbit model it was bactericidal at 6 h against the susceptible strain, but against the resistant 3/8 therapeutical failures were recorded at 6 h, being bactericidal at 24 h. In conclusion, meropenem has shown bactericidal activity in both experimental models. This work emphasises the importance of an adequate election of the animal model for the appropriate development of studies of antimicrobial efficacy. We believe that guinea pig should be considered the best choice among laboratory animal species when assessing meropenem efficacy.

Experimental study of teicoplanin, alone and in combination, in the therapy of cephalosporin-resistant pneumococcal meningitis.

OBJECTIVES: The aim of the study was to determine the efficacy of teicoplanin, alone and in combination with ceftriaxone, in a rabbit model of cephalosporin-resistant pneumococcal meningitis, and to assess the effect of concomitant therapy with dexamethasone. METHODS: In vitro killing curves of teicoplanin, with and without ceftriaxone, were performed. Groups of eight animals per treatment were inoculated with a cephalosporin-resistant pneumococcal strain (penicillin MIC, 4 mg/L; ceftriaxone MIC, 2 mg/L; teicoplanin MIC, 0.03 mg/L) and treated over a 26 h period. Teicoplanin was administered at a dose of 15 mg/kg, alone and in combination with ceftriaxone at 100 mg/kg with or without dexamethasone at 0.25 mg/kg. CSF samples were collected at different time-points, and bacterial titres, white blood cell counts, lactate and protein concentrations and bacteriostatic/bactericidal titres were determined. Blood and CSF teicoplanin pharmacokinetic and pharmacodynamic parameters were determined. RESULTS: Teicoplanin alone promoted a decrease in bacterial counts at 6 h of -2.66 log cfu/mL and was bactericidal at 24 h, without therapeutic failures. Similar good results were obtained when dexamethasone was used simultaneously, in spite of the penetration of teicoplanin into the CSF being significantly reduced, from 2.31% to 0.71%. Teicoplanin and ceftriaxone combinations were synergic in vitro, but not in the meningitis model. CONCLUSIONS: Teicoplanin alone was very effective in this model of cephalosporin-resistant pneumococcal meningitis. The use of concomitant dexamethasone resulted in lower CSF teicoplanin levels, but not in therapeutic failures. The combination of teicoplanin plus ceftriaxone and dexamethasone might be a good alternative for the empirical therapy of pneumococcal meningitis. Additional data should confirm our experiments, in advance of clinical trials to assess efficacy in humans.

Relationship between penicillin and cephalosporin resistance of Streptococcus pneumoniae strains and its inflammatory activity in the experimental model of meningitis.

Using a rabbit model of meningitis, we sought to compare the inflammatory activity induced by three pneumococcal strains with different susceptibilities to penicillin and cephalosporins, belonging to the serotypes 3, 6B and 23F at different inoculum sizes. These serotypes are prevalent in Western Europe and are believed to produce a moderate-to-severe cerebrospinal fluid (CSF) inflammatory response. Only minor differences were observed in the inflammatory activity evoked by the three strains in the subarachnoid space, and most were probably related to differences in bacterial counts. Infection by serotype 23F caused secondary bacteremia in all challenged animals. Our findings reinforce the concept that resistant pneumococci are not more virulent, a fact that should be taken into account when evaluating the efficacy of different anti-pneumococcal therapies. However, the frequent induction of secondary bacteremia by the resistant serotype 23F requires further study.

Streptococcal meningitis in adult patients: current epidemiology and clinical spectrum.

Streptococci other than Streptococcus pneumoniae are a rare cause of bacterial meningitis in adults. We report 29 cases of streptococcal meningitis (1977-1997). The patients comprised 19 men and 10 women, with a mean age +/- standard deviation of 47 +/- 18 years. Nine cases were secondary to neurosurgical procedures, seven to brain abscess, five to cerebrospinal fluid pericranial fistula, and three to endocarditis. Causative microorganisms included the following: viridans group streptococci, 20 cases; anaerobic streptococci, 3; Streptococcus agalactiae, 3; Streptococcus bovis, 2; and Streptococcus pyogenes, 1. Four Streptococcus mitis strains showed decreased susceptibility to penicillin (MIC, 0.5-2 microg/mL). Five patients (17%) died. The infection is increasing in the hospital setting. Streptococci resistant to penicillin should be considered in the empirical treatment of nosocomial meningitis. In cases of community-acquired infection, anaerobic streptococci or streptococci of the Streptococcus milleri group should alert the clinician to the presence of an undiagnosed brain abscess, whereas oral streptococci of the viridans group suggest the diagnosis of bacterial endocarditis.

Streptococcus bovis meningitis in a healthy adult patient.

We describe the first case in the English language of Streptococcus bovis meningitis in a 45-y-old patient without any underlying disease or predisposing condition. S. bovis biotype II was isolated from his spinal fluid and blood. The illness was community-acquired and was clinically and biologically similar to disease caused by the classical meningeal pathogens. The patient was cured after 10 d of therapy with ceftriaxone and, 2.5 y later, is currently healthy. As a result of this case and a similar case published recently in the Spanish literature we conclude that S. bovis should be considered a microorganism capable of causing meningitis in the absence of any underlying condition or clear focus of infection.

A single daily dose of ceftriaxone for bacterial meningitis in adults: experience with 84 patients and review of the literature.

Although the pharmacokinetics of ceftriaxone allows its administration in a single daily dose, this practice is not standard in the treatment of bacterial meningitis. Herein, we review our experience and that of other investigators with this mode of therapy. We used a single daily dose of ceftriaxone (50 mg/[kg.d]; maximum, 4 g/d) for the treatment of bacterial meningitis in 84 adult patients. Meningitis was due to Neisseria meningitidis in 34 cases, to Streptococcus pneumoniae in 25, to Escherichia coli in three, to Klebsiella pneumoniae in two, to Haemophilus influenzae in two, to viridans streptococci in two, and to an unknown agent in 16. Eleven patients died, for an overall mortality of 13%; therapy failed in three additional cases. The mean trough levels of ceftriaxone in cerebrospinal fluid was 3.5 micrograms/mL; the median trough bactericidal titer at this site was 1:128. Both our experience and that in the literature suggest that a single daily dose is optimal when ceftriaxone is used for the treatment of bacterial meningitis.

[Protective effect of dexamethasone and phenytoin in the treatment of experimental pneumococcal meningitis]. / Efecto protector de dexametasona y fenitoína en el tratamiento de la meningitis neumocócica experimental.

BACKGROUND: Pneumococcal meningitis has a high morbidity and mortality rate despite effective antibiotherapy, probably due to an exaggerated inflammatory response of the CNS. The use of dexamethasone and phenytoin reduced mortality in adults with pneumococcal meningitis. OBJECTIVE: We sought to determine the effect of dexamethasone, phenytoin or the association of both in several inflammatory parameters in experimental bacterial meningitis. METHODS: The study was performed using a modification of the rabbit model of Dacey and Sande. New Zealand white rabbits were intracisteranly inoculated simultaneously with heat-killed S. pneumoniae R6 dexamethasone, phenytoin or both. CSF leucocytes and concentration of proteins and lactate were determined over 6 hours, as well as the presence of brain edema. RESULTS: Treatment with dexamethasone alone or in association with phenytoin reduced all inflammatory parameters. The administration of phenytoin alone did not prevent an increase of CSF leucocytes or protein concentration, but did prevent the development of brain edema. A trend to wards a protective effect on the lactate concentration was observed. CONCLUSIONS: Our results gives support to the antiinflammatory effect of dexamethasone in experimental pneumococcal meningitis, and suggest that phenytoin may have also a protective effect on brain ischemia. This protective action and the prevention of brain edema could contribute, beyond its anticonvulsivant properties, to the great reduction in the mortality rate observed in some clinical studies in patients with pneumococcal meningitis.

Relevance of in vitro antimicrobial susceptibility of Brucella melitensis to relapse rate in human brucellosis.

The in vitro susceptibility of Brucella melitensis was examined vis-a-vis the clinical outcome in 75 patients with brucellosis. The initial MICs for Brucella isolates from patients who relapsed and from those who did not were similar. Furthermore, the MICs for isolates from patients whose infections relapsed were no different from those for original isolates. Our results clearly showed that neither initial nor subsequent antibiotic susceptibility plays a role in the likelihood of relapse of patients with brucellosis.

Evaluation of combined ceftriaxone and dexamethasone therapy in experimental cephalosporin-resistant pneumococcal meningitis.

The treatment of meningitis caused by strains of Streptococcus pneumoniae with decreased susceptibility to third-generation cephalosporins is an increasingly frequent and difficult problem. In this study a rabbit model of meningitis was used to determine the efficacy of ceftriaxone at different dosages, and to establish the effect of the addition of dexamethasone to the chemotherapeutic regimen. Groups of eight rabbits were inoculated with 10(6) cfu/mL of a cephalosporin- resistant strain of S. pneumoniae (MIC of cefotaxime/ceftriaxone 2 mg/L). Eighteen hours after inoculation, ceftriaxone (50 or 100 mg/kg/day) with or without dexamethasone (0. 25 mg/kg/ day) was administered for a period of 48 h. The ceftriaxone dose of 50 mg/kg/day was not fully effective in this model (therapeutic failure rate 28%). With a dose of 100 mg/kg/day there were no therapeutic failures and all CSF cultures were below the level of detection at 48 h. CSF ceftriaxone concentrations, area under the time-concentration curve and time above the MIC were not significantly different with or without dexamethasone. However, concomitant use of dexamethasone resulted in higher CSF bacterial counts and a higher number of therapeutic failures (57% with the 50 mg/kg/day dose and 28% with the 100 mg/kg/day dose). Increasing doses of ceftriaxone might be an effective mode of therapy for meningitis caused by S. pneumoniae with MIC