The results of this study, in which dexamethasone administration began before the initiation of cefotaxime therapy, provide additional evidence of a beneficial effect of dexamethasone therapy in infants and children with bacterial meningitis.

The most appropriate therapy for meningitis caused by Streptococcus pneumoniae strains resistant to the extended-spectrum cephalosporins is unknown. We evaluated ceftriaxone, vancomycin, and rifampin alone and in different combinations and meropenem, cefpirome, and clinafloxacin alone in the rabbit meningitis model. Meningitis was induced in rabbits by intracisternal inoculation of one of two pneumococcal strains isolated from infants with meningitis (ceftriaxone MICs, 4 and 1 ,g/ml, respectively). Two doses, 5 h apart, of each antibiotic were given intravenously (except that ceftriaxone was given as one dose). Cerebrospinal fluid bacterial concentrations were measured at 0, 5, 10, and 24 h after therapy was started. Clinafloxacin was the most active single agent against both strains. Against the more resistant strain, ceftriaxone or meropenem alone was ineffective. The combination of vancomycin and ceftriaxone was synergistic, suggesting that this combination might be effective for initial empiric therapy of pneumococcal meningitis until results of susceptibility studies are available.

A monoclonal antibody (MAb) to Moraxella catarrhalis O35E bound to a surface-exposed epitope of a proteinaceous antigen of this organism. The antigen, designated UspA, was present in every strain of the pathogen tested in a colony blot RIA. UspA had a molecular mass on SDS-PAGE that varied between 300 and 400 kDa, depending on the individual M. catarrhalis strain. Passive immunization of mice with the UspA-reactive Mab enhanced pulmonary clearance of M. catarrhalis. Use of this Mab to screen a M. catarrhalis genomic DNA library permitted identification of a recombinant bacteriophage expressing the M. catarrhalis UspA protein. The recombinant UspA protein was used in Western blot analysis with sera from patients with M. catarrhalis pneumonia. Convalescent-phase sera but not acute-phase sera from these patients contained antibodies to this M. catarrhalis surface protein, indicating that M. catarrhalis strains growing in vivo express this molecule.

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Treatment of pneumococcal meningitis has become problematic because of the emergence of penicillin-and cephalosporin-resistant strains and because of the concern that dexamethasone therapy might reduce penetration of antibiotics into the cerebrospinal fluid (CSF). We addressed these issues with our rabbit meningitis model by studying two pneumococcal isolates that were resistant to penicillin and ceftriaxone and susceptible to vancomycin and rifampin. Ceftriaxone, vancomycin, and rifampin were given alone or in combination, with or without coadministration of dexamethasone. Treatment was started 12 to 14 h after intracisternal inoculation of i104 CFU of one of the organisms. Rifampin concentrations in serum and CSF were similar, regardless of whether dexamethasone was given, whereas those of ceftriaxone were somewhat lower at each time point in animals given dexamethasone. The penetration of vancomycin into CSF was consistently and substantially reduced with dexamethasone treatment, which resulted in a delay in CSF sterilization not observed in non-dexamethasone-treated animals. When rifampin was used with ceftriaxone for treatment of meningitis caused by the more resistant strain, bacteriologic cure occurred promptly, with or without dexamethasone therapy. In areas with high rates of occurrence of resistant pneumococcal strains, we believe initial empiric therapy of bacterial meningitis should include two antibiotics: ceftriaxone and either rifampin or vancomycin. When dexamethasone is used, the combination of ceftriaxone and rifampin is preferred for therapy.Dexamethasone has been shown to improve the long-term outcome in infants and children with bacterial meningitis, especially meningitis caused by Haemophilus influenzae type b (19,20,27,28). Its role in the management of Streptococcus pneumoniae meningitis is uncertain, although a retrospective study of 97 infants and children (18) and a prospective trial in 106 older patients (15) with pneumococcal meningitis suggested a satisfactory effect. With routine use of conjugate Haemophilus vaccines in many countries, meningitis caused by this organism has virtually disappeared (1,4,6,23,26,29), leaving the pneumococcus and meningococcus as the principal causes of meningitis in these areas.Attention has recently focused on management of pneumococcal meningitis because of the emergence of penicillin-and cephalosporin-resistant strains (7,8,10,11 (214) 648-2961. showed synergistic killing of resistant pneumococci in the rabbit meningitis model (12), and this regimen has been suggested for routine initial therapy of bacterial meningitis until results of culture and susceptibility studies are available.Because of concerns about the highly variable concentrations of vancomycin in cerebrospinal fluid (CSF) after parenteral administration (22,34) and about possible reduced penetration of vancomycin into CSF when dexamethasone is concomitantly given, the present study was undertaken. The impact of dexamethasone therapy on the decrease of clearance of resistant pneum...

ObjectivesThe PALACE 4 trial evaluated apremilast monotherapy in patients with active PsA who were DMARD-naive.MethodsEligible patients were randomized (1:1:1) to placebo, apremilast 20 mg twice a day or apremilast 30 mg twice a day. At week 16 or 24, placebo patients were rerandomized to apremilast. Double-blind apremilast treatment continued to week 52, with extension up to 4 years. The primary endpoint was the proportion of patients achieving ⩾20% improvement in ACR response criteria (ACR20) at week 16; secondary endpoints included the mean change in the HAQ Disability Index (HAQ-DI) score at week 16.ResultsA total of 527 patients with mean disease duration of 3.4 years and high disease activity were randomized and received treatment. More apremilast patients achieved ACR20 response at week 16 [placebo, 15.9%; 20 mg, 28.0% (P = 0.0062); 30 mg, 30.7% (P = 0.0010)]. The mean HAQ-DI improvements were −0.17 (20 mg; P = 0.0008) and −0.21 (30 mg; P < 0.0001) vs 0.03 (placebo). Both apremilast doses showed significant ACR50 responses vs placebo at week 16 and improvements in secondary efficacy measures (swollen/tender joint counts) and psoriasis assessments, with sustained improvements through week 52. Common adverse events (AEs) over 52 weeks were diarrhoea, nausea, headache and upper respiratory tract infection; most events were mild or moderate. Serious AEs and AEs leading to discontinuation were comparable between groups. Laboratory abnormalities were infrequent and transient.ConclusionsIn DMARD-naive patients, apremilast monotherapy improved PsA signs/symptoms over 52 weeks and was generally well tolerated.Trial registrationClinicalTrials.gov (http://clinicaltrials.gov), NCT01307423.

A major outer membrane protein (CopB) of Moraxella catarrhalis is a target for antibodies that enhance clearance of this organism from the lungs of mice. A mini-Tn10kan transposon was inserted into the cloned copB gene from M. catarrhalis O35E, and an isogenic mutant unable to express the CopB protein was constructed by transforming this mutated gene into the wild-type strain. The mutant grew at the same rate as the wild-type parent strain in broth. Unlike the serum-resistant parent strain, this mutant was sensitive to killing by normal human serum, and its ability to survive and grow in the lungs of animals was impaired. Genetic restoration of CopB protein expression resulted in the simultaneous acquisition of wild-type levels of serum resistance and the ability to resist pulmonary clearance in vivo. Thus, the CopB protein of M. catarrhalis may be important in the interaction between this organism and the defense mechanisms of the respiratory tract.

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