Pedro F. Viladrich

Resistance to Penicillin and Cephalosporin and Mortality from Severe Pneumococcal Pneumonia in Barcelona, Spain

BACKGROUND Penicillin-resistant strains of Streptococcus pneumoniae are now found worldwide, and strains with resistance to cephalosporin are being reported. The appropriate antibiotic therapy for pneumococcal pneumonia due to resistant strains remains controversial. METHODS To examine the effect of resistance to penicillin and cephalosporin on mortality, we conducted a 10-year, prospective study in Barcelona of 504 adults with culture-proved pneumococcal pneumonia. RESULTS Among the 504 patients, 145 (29 percent) had penicillin-resistant strains of S. pneumoniae (minimal inhibitory concentration [MIC] of penicillin G, 0.12 to 4.0 micrograms per milliliter), and 31 patients (6 percent) had cephalosporin-resistant strains (MIC of ceftriaxone or cefotaxime, 1.0 to 4.0 micrograms per milliliter). Mortality was 38 percent in patients with penicillin-resistant strains, as compared with 24 percent in patients with penicillin-sensitive strains (P = 0.001). However, after the exclusion of patients with polymicrobial pneumonia and adjustment for other predictors of mortality, the odds ratio for mortality in patients with penicillin-resistant strains was 1.0 (95 percent confidence interval, 0.5 to 1.9; P = 0.84). Among patients treated with penicillin G or ampicillin, the mortality was 25 percent in the 24 with penicillin-resistant strains and 19 percent in the 126 with penicillin-sensitive strains (P = 0.51). Among patients treated with ceftriaxone or cefotaxime, the mortality was 22 percent in the 59 with penicillin-resistant strains and 25 percent in the 127 with penicillin-sensitive strains (P = 0.64) The frequency of resistance to cephalosporin increased from 2 percent in 1984-1988 to 9 percent in 1989-1993 (P = 0.002). Mortality was 26 percent in patients with cephalosporin-resistant S. pneumoniae and 28 percent in patients with susceptible organisms (P = 0.89). Among patients treated with ceftriaxone or cefotaxime, mortality was 22 percent in the 18 with cephalosporin-resistant strains and 24 percent in the 168 with cephalosporin-sensitive organisms (P = 0.64). CONCLUSIONS Current levels of resistance to penicillin and cephalosporin by S. pneumoniae are not associated with increased mortality in patients with pneumococcal pneumonia. Hence, these antibiotics remain the therapy of choice for this disease.

Risk Factors and Response to Antibiotic Therapy in Adults with Bacteremic Pneumonia Caused by Penicillin-Resistant Pneumococci

We retrospectively studied 24 adults with bacteremic pneumonia (25 episodes) due to penicillin-resistant pneumococci, for which the minimal inhibitory concentrations (MICs) of penicillin G were 0.12 to 8.0 micrograms per milliliter; 79 percent of the strains showed multiple antibiotic resistance. As compared with 48 control patients with bacteremic pneumonia caused by penicillin-sensitive pneumococci, the 24 patients with penicillin-resistant pneumococci had a significantly higher incidence of use of beta-lactam antibiotics during the previous three months (65 vs. 17 percent, P = 0.0008), hospitalization during the previous three months (58 vs. 21 percent, P = 0.0038), nosocomial pneumonia (37 vs. 6 percent, P = 0.0032), episodes of pneumonia during the previous year (29 vs. 4 percent, P = 0.010), and factors on initial presentation that were associated with a poor prognosis (an initially critical condition) (67 vs. 27 percent, P = 0.0030). Their overall mortality rate was significantly higher (54 vs. 25 percent, P = 0.0298). Eleven of 19 episodes of pneumonia due to organisms for which MICs were 0.12 to 2.0 micrograms per milliliter, which were treated with penicillin G (10 episodes) or another beta-lactam agent (9 episodes), resulted in recovery (2 of 10 patients in an initially critical condition recovered, as compared with all of 9 not initially in a critical condition, P = 0.0012). Two patients who had penicillin-resistant pneumococci for which MICs were 4.0 and 8.0 micrograms per milliliter did not respond to ampicillin and ticarcillin therapy, respectively. Our study suggests that pneumonia due to penicillin-resistant pneumococci may occur more often in a population with some identifiable risk factors, and may respond to intravenous high-dose penicillin therapy if MICs are less than or equal to 2 micrograms per milliliter. Cases involving higher resistance may require an alternative antibiotic.

Evaluation of vancomycin for therapy of adult pneumococcal meningitis.

The emergence of pneumococci resistant to penicillin and other agents prompted us to evaluate intravenous vancomycin for the therapy of pneumococcal meningitis, which has an overall mortality of 30%. Eleven consecutive adult patients with cerebrospinal fluid (CSF)-culture-proven pneumococcal meningitis and positive initial CSF Gram stain were given intravenous vancomycin (usual dosage, 7.5 mg/kg every 6 h for 10 days). The MBCs of vancomycin ranged from 0.25 to 0.5 micrograms/ml. Early adjunctive therapy with intravenous dexamethasone, mannitol, and sodium phenytoin was also instituted. After 48 h of therapy, all 11 patients showed a satisfactory clinical response, although the CSF culture remained positive in one case; median trough CSF and serum vancomycin levels were 2 and 5.1 micrograms/ml, respectively, and trough CSF bactericidal titers ranged from less than 1:2 to 1:16. On day 3, one patient died of acute heart failure. Four patients had clinical failure at on days 4 (two patients), 7 (one), and 8 (one) of therapy; they all immediately responded to a change in antibiotic therapy. The remaining six patients were cured after 10 days of vancomycin therapy. At this point, median peak CSF and serum vancomycin levels were 1.9 and 18.5 micrograms/ml, respectively. A transient alteration of renal function occurred in two patients, and persistent slight hypoacusia occurred in three patients. In summary, 11 adults with pneumococcal meningitis were treated with vancomycin and early adjunctive therapy including dexamethasone. All patients initially improved, and 10 were ultimately cured of the infection. However, four patients experienced a therapeutic failure, which led to a change in vancomycin therapy.

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.

Treatment of Human Brucellosis with Doxycycline plus Rifampin or Doxycycline plus Streptomycin: A Randomized, Double-Blind Study

OBJECTIVE To compare the effectiveness of doxycycline-rifampin (DR) combination therapy with that of the classic doxycycline-streptomycin (DS) combination in patients with brucellosis. DESIGN A randomized, double-blind study, with a mean follow-up of 15.7 months. SETTING A 1000-bed teaching hospital in Barcelona, Spain. PATIENTS Ninety-five patients (68 men and 27 women; mean age, 39 years) diagnosed with brucellosis on the basis of both clinical and serologic findings; 81 of these patients had blood cultures positive for Brucella melitensis. INTERVENTIONS Forty-four patients received doxycycline, 100 mg every 12 hours, and rifampin, 15 mg/kg body weight per day in a single morning dose, for 45 days; 51 patients received the same dose of doxycycline for 45 days plus streptomycin, 1 g/d for 15 days. MAIN OUTCOME MEASURES Therapeutic failure and relapse during the follow-up period. RESULTS The mean time to defervescence was 4.2 days for the DR group and 3.2 days for the DS group (P greater than 0.2). The actuarial probability of therapeutic failure or relapse at 12 months of follow-up (Kaplan-Meier) was 14.4% in the DR group and 5.9% in the DS group (difference, 8.5%; 95% Cl, -4.8% to 21.6%; P greater than 0.2). All three patients with spondylitis in the DR group failed therapy compared with one of four patients in the DS group. Excluding patients with spondylitis, the actuarial failure rate was 4.9% and 4.3% in the DR and DS groups, respectively, at 12 months of follow-up (difference, 0.6%; Cl, -8.1% to 9.4%; P greater than 0.2). CONCLUSIONS Doxycycline-rifampin combination therapy for 45 days is as effective as the classic DS combination in most patients with brucellosis; however, DR therapy might be less effective in those patients with spondylitis.

Influence of dexamethasone on efficacy of ceftriaxone and vancomycin therapy in experimental pneumococcal meningitis.

Using a rabbit model of meningitis, we sought to determine whether concomitant use of dexamethasone affects the penetration and efficacy of ceftriaxone or vancomycin in cerebrospinal fluid. Rabbits were inoculated with a penicillin-sensitive strain of Streptococcus pneumoniae and treated with ceftriaxone or vancomycin with or without dexamethasone. In the ceftriaxone-treated groups, no statistically significant differences were seen between the group treated with dexamethasone and that without dexamethasone; however, in the vancomycin-treated groups we found statistically significant lower cerebrospinal fluid vancomycin levels at 2 h in the dexamethasone-treated rabbits and differences in bacterial killing.

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.

Community-acquired bacterial meningitis in elderly patients: experience over 30 years.

Clinical characteristics, etiologies, evolution, and prognostic factors of community-acquired bacterial meningitis in elderly patients are not well known. To improve this knowledge, all episodes of community-acquired bacterial meningitis were prospectively recorded and cases occurring in patients ≥65 years old were selected. During the period 1977-2006, 675 episodes in adults (aged ≥18 yr) were recorded, with 185 (27%) in patients aged ≥65 years old; 76 were male and 109 were female, with a mean age of 73 ± 6 years (range, 65-93 yr). Causative microorganisms were Streptococcus pneumoniae 74, Neisseria meningitidis 49, Listeria monocytogenes 17, other streptococcal 9, Escherichia coli 6, Haemophilus influenzae 4, Klebsiella pneumoniae and Staphylococcus aureus 2 each, Capnocytophaga canimorsus and Enterococcus faecalis 1 each, and unknown in 20. On admission 91% had had fever, 32% were in a coma (Glasgow Coma Scale ≤8), 9% presented with seizures, and 8% with shock. Thirty patients (16%) presented with seizures during therapy. Mortality was 58/185 (31%). Compared with patients aged 18-65 years, there were significant differences among older patients (aged ≥65 yr), who showed a higher frequency of diabetes and malignancy as underlying disease; pneumonia, otitis, and pericranial fistula as predisposing factors; and S. pneumoniae and L. monocytogenes as etiology. There were also differences in clinical presentation, complications, sequelae, and mortality. Factors independently related with mortality were age, pneumonia as a predisposing factor, coma on admission, and heart failure and seizures after therapy. Dexamethasone therapy was a protective factor. In conclusion, bacterial meningitis in elderly patients is associated with greater diagnostic difficulties and neurologic severity and more complications, as well as with increased mortality. Antiseizure prophylaxis might be useful in these patients. Abbreviations: CSF = cerebrospinal fluid, ICP = intracranial pressure.

West Nile virus in Spain : Report of the first diagnosed case (in Spain) in a human with aseptic meningitis

We report the first case of illness caused by West Nile virus (WNV) so far diagnosed in Spain. A 21-y-old male presented with clinical and biological signs compatible with viral meningitis. Acute and convalescent serum samples showed IgM and IgG positivity for WNV. These results were confirmed by microneutralization assays.

Characteristics of meningitis caused by Ibuprofen: report of 2 cases with recurrent episodes and review of the literature.

Abstract: Ibuprofen is a common nonsteroidal antiinflammatory drug that is the most frequent cause of aseptic meningitis induced by drugs. The incidence of this type of aseptic meningitis is increasing, mainly among patients with underlying autoimmune connective tissue disorder, but also among healthy people. We report 2 patients with recurrent meningitis caused by ibuprofen mimicking bacterial meningitis: the first patient a woman with dermatomyositis and the second patient a previously healthy woman who developed autoimmune thyroiditis a few months later. We then review 71 episodes of ibuprofen-related meningitis in 36 patients reported in the literature. Twenty-two patients (61%) presented with an autoimmune connective tissue disorder, mainly systemic lupus erythematosus, and 22 (61%) had recurrent episodes. Most episodes consisted of an acute meningeal syndrome with a predominance of neutrophils in cerebrospinal fluid (CSF) in 72.2% of episodes and elevated protein in the CSF, so the clinical presentation of this type of aseptic meningitis may be quite similar to that of acute bacterial meningitis. CSF glucose levels are usually normal, which may help to differentiate between these 2 types of meningitis. In some cases the clinical presentation is that of meningoencephalitis with neurologic focal deficits. Although based on the close relation between the administration of ibuprofen and the onset of symptoms, especially if previous episodes have occurred, the diagnosis of ibuprofen-induced aseptic meningitis is a diagnosis by exclusion. If the clinical picture is compatible with bacterial meningitis, empirical antibiotic therapy must be administered until negativity of cultures and other microbiologic tests is determined. Rechallenge to ibuprofen reproduces the symptoms and confirms the diagnosis, but is usually not advised. Whatever the clinical presentation, physicians must consider the possibility of ibuprofen-related meningitis or meningoencephalitis in patients taking ibuprofen, especially if they are suffering from an autoimmune connective tissue disorder. On the other hand, we think it would be appropriate to screen for autoimmune disease in previously healthy patients diagnosed with ibuprofen-related meningitis or meningoencephalitis. Finally, we propose that meningitis due to ibuprofen be included in the list of causes of recurrent aseptic meningitis. Abbreviations: CNS = central nervous system, CSF = cerebrospinal fluid, CT = computerized tomography, ICU = intensive care unit, NSAID = nonsteriodal antiinflamatory drug, SLE = systemic lupus erythematosus, WBC = white blood cells.