Matrix metalloproteinase (MMP)-8 and MMP-9 in cerebrospinal fluid during bacterial meningitis: association with blood-brain barrier damage and neurological sequelae.

To evaluate the spectrum and regulation of matrix metalloproteinases (MMPs) in bacterial meningitis (BM), concentrations of MMP-2, MMP-3, MMP-8, and MMP-9 and endogenous inhibitors of metalloproteinases (TIMP-1 and TIMP-2) were measured in the cerebrospinal fluid (CSF) of 27 children with BM. MMP-8 and MMP-9 were detected in 91% and 97%, respectively, of CSF specimens from patients but were not detected in control patients. CSF levels of MMP-9 were higher (P<.05) in 5 patients who developed hearing impairment or secondary epilepsy than in those who recovered without neurological deficits. Levels of MMP-9 correlated with concentrations of TIMP-1 (P<.001) and tumor necrosis factor-alpha (P=.03). Repeated lumbar punctures showed that levels of MMP-8 and MMP-9 were regulated independently and did not correlate with the CSF cell count. Therefore, MMPs may derive not only from granulocytes infiltrating the CSF space but also from parenchymal cells of the meninges and brain. High concentrations of MMP-9 are a risk factor for the development of postmeningitidal neurological sequelae.

Comparison of immunogenicity and safety of a virosome influenza vaccine with those of a subunit influenza vaccine in pediatric patients with cystic fibrosis.

The objective of this study was to compare the immunogenicity and safety of a single-dose regimen and a two-dose regimen of a trivalent virosome influenza vaccine (Inflexal Berna V) with those of a trivalent subunit influenza vaccine (Influvac) in children and adolescents with cystic fibrosis (CF). In an open, randomized, multicenter study with parallel groups, 11 young children with CF (1 to 6 years old) and 53 older children and adolescents with CF (>6 years old) were randomly assigned to one of the following immunization regimens: virosome vaccine at 0.5 ml on study day 0 or 0.25 ml on days 0 and 28 or a standard regimen of subunit vaccine, i. e., 0.5 ml on day 0 for older children and 0.25 ml on days 0 and 28 for younger children. Safety assessments, i.e., recording of systemic and local adverse events (AEs) and vital signs, were made for a 5-day observation period after each immunization. Hemagglutination inhibition (HI) titers were determined at baseline and 4 weeks after the single-dose and the two-dose immunizations, respectively. Immunogenicity was assessed according to the criteria of the European Agency for the Evaluation of Medicinal Products (EMEA). Both vaccines induced comparable HI antibody titers. Seroconversion (> or =4-fold rise in HI antibody titers, reaching a titer of > or =1:40) was achieved in 41 to 100% of the participants. Seroprotection (HI titer, > or =1:40) and a >2.5-fold increase in geometric mean titers were achieved in 100% of the participants. Thus, all three EMEA requirements for influenza vaccine efficacy were met by all treatment groups and for both vaccines. The virosome vaccine, when administered as a single dose, seemed to induce superior immunogenicity compared with the standard pediatric two-dose regimen. Totals of 42 and 57% of vaccinees receiving virosome and subunit vaccines, respectively, reported at least one local AE (predominantly pain). Totals of 84 and 71% of subjects receiving virosome and subunit vaccines, respectively, complained in response to questions of at least one systemic AE (mainly cough, fatigue, coryza, or headache). The majority of events were mild or moderate and lasted 1 or 2 days only. No obvious relationship was found between AE reporting rate and vaccine formulation, age group, or dose regimen. The relatively high AE reporting rate seemed to be partly related to the symptomatology of the underlying CF disease. In summary, the virosome and subunit vaccines induced in both age groups and against all three influenza strains an efficient immune response and were well tolerated by the children and adolescents with CF.

Oral ciprofloxacin vs. intravenous ceftazidime plus tobramycin in pediatric cystic fibrosis patients: comparison of antipseudomonas efficacy and assessment of safety with ultrasonography and magnetic resonance imaging. Cystic Fibrosis Study Group.

BACKGROUND: More data on the efficacy and safety of ciprofloxacin in pediatric cystic fibrosis patients are needed. METHODS: One hundred eight pediatric cystic fibrosis patients (ages 5 to 17 years) with acute bronchopulmonary exacerbations entered a randomized multicenter trial designed to compare the safety and efficacy of antipseudomonas therapy with oral ciprofloxacin (15 mg/kg twice daily; maximum dosage 750 mg twice daily) or intravenous ceftazidime plus tobramycin (CAZ/TM) for 14 days. RESULTS: Clinical improvement was observed in 93% of patients treated with oral ciprofloxacin and in 96% of those receiving parenteral therapy. Transient suppression of Pseudomonas aeruginosa was achieved in 63% of patients at the end of the course of iv CAZ/TM therapy and in 24% receiving ciprofloxacin. Ultrasound examination and nuclear magnetic resonance imaging scans showed no evidence of cartilage toxicity in any of the ciprofloxacin-treated patients. Musculoskeletal adverse events were reported with similar frequency in the two groups of patients (7% in the group receiving ciprofloxacin therapy and 11% in the IV CAZ/TM group). The only sustained musculoskeletal symptom was a case of synovitis in a patient receiving parenteral CAZ/TM. CONCLUSION: Ciprofloxacin thus appears to be safe and effective for use in young patients with bronchopulmonary exacerbation of cystic fibrosis.

Ciprofloxacin as antipseudomonal treatment in patients with cystic fibrosis.

OBJECTIVE: The efficacy and safety of oral ciprofloxacin as a maintenance antipseudomonal therapy were evaluated in 44 patients with cystic fibrosis who had completed a 14-day regimen of intensive hospital therapy with intravenous ceftazidime and amikacin, supplemented by amikacin inhalation therapy. METHODS: Twenty-one patients were randomly assigned to oral ciprofloxacin alone (Group I) and 23 received ciprofloxacin plus inhaled amikacin (Group II). RESULTS: Negative sputum cultures were achieved in 34 patients (77%) at the end of intensive therapy (19 Group I and 15 Group II) and were sustained after 3 months of maintenance therapy in 5 of the 19 responders in Group I (26%) and in 8 of the 15 responders in Group II (53%). Resistance to ciprofloxacin was found in 7 of 31 (23%) sputum isolates at the end of ciprofloxacin therapy. During maintenance therapy, continued improvement in clinical symptoms was observed in 14 patients in both treatment groups; 6 in each group had further improvements whereas only 4 patients were clinical failures. There was no correlation between clinical outcome and either elimination of Pseudomonas aeruginosa from sputum culture or development of ciprofloxacin resistance. Both maintenance regimens were well-tolerated by this population of patients which included 28 children younger than 15 years of age. There were no severe or serious adverse events, no signs of quinolone-related arthropathy and no growth impairment. CONCLUSION: Ciprofloxacin was efficacious, safe and well-tolerated as maintenance antipseudomonal therapy in cystic fibrosis patients. These results suggest further evaluation of ciprofloxacin as an oral maintenance therapy is warranted.

Pharmacokinetics of ciprofloxacin in pediatric cystic fibrosis patients.

The pharmacokinetic characteristics of ciprofloxacin were studied in 10 children with cystic fibrosis, aged from 6 to 16 years, who had completed the standard regimen of intravenous ceftazidime and amikacin. The aim of the investigation was to derive dosing guidelines for young cystic fibrosis patients to be treated with ciprofloxacin. Each child received ciprofloxacin given as two 30-min infusions (10 mg/kg of body weight each) 12 h apart; this was followed by the administration of oral ciprofloxacin (15 mg/kg every 12 h). Blood samples were taken after both infusions and after the first oral dose. A total of 232 ciprofloxacin concentrations (203 concentrations in plasma and 29 concentrations in urine) were analyzed by use of NONMEM and a two-compartment body model with seven parameters: total body clearance (CL), volume of the central compartment (V2), volume of the peripheral compartment (V3), intercompartmental clearance, renal clearance, absorption rate constant, and bioavailability. The influences of weight (range, 18 to 42 kg) and age (range, 6 to 16 years) were investigated. CL (in liters per hour) was found to be linearly correlated with weight (typical value of CL = 8.8 + 0.396. WT, where WT is weight; (interindividual coefficient of variation, 7.8%). V2 and V3 were directly proportional to weight, with slopes of 0.7 and 1.3 liters/kg, respectively. Interindividual variabilities were calculated to be 22.6 and 14.9% for V2 and V3, respectively. No dependency of the other pharmacokinetic parameters on age or weight was seen. Because of the high correlations between age and weight, only one covariable was necessary. Weight had the strongest effect. Bioavailability (population mean) was estimated to be 61.8%, and renal clearance (population mean) was estimated to be 11.4 liters/h. The residual (intraindividual) variability was 31.9%. The protein binding was about 34%, which is similar to the results obtained for adults. In order to define the appropriate dosage regimen for children suffering from cystic fibrosis, a formula was derived so that steady-state concentrations, similar to those obtained in adults after the administration of dosages of 400 mg three times daily intravenously and 750 mg twice daily orally, could be reached. The calculated total daily dose increased with increasing body weight. Given as milligrams per kilogram of body weight, the calculated dosage regimens suggest that for younger children (weight range, 14 to 28 kg), 28 to 20 mg/kg orally twice daily should be given, and for older children (weight range, 28 to 42 kg), 20 to 15 mg/kg orally twice daily should be given. For intravenous administration, dosages of 15 to 10 mg/kg twice daily are sufficient.

Effect of high-affinity anti-Pseudomonas aeruginosa lipopolysaccharide antibodies induced by immunization on the rate of Pseudomonas aeruginosa infection in patients with cystic fibrosis.

Patients with cystic fibrosis (CF; N = 26) and with no prior history of infection with Pseudomonas aeruginosa were immunized with an octavalent O-polysaccharide-toxin A conjugate vaccine. During the next 4 years, 16 patients (61.5%) remained free of infection and 10 (38.5%) became infected. Total serum antilipopolysaccharide (LPS) antibody levels induced by immunization were comparable in infected and noninfected patients. In contrast, 12 of 16 noninfected versus 3 of 10 infected patients (p = 0.024) mounted and maintained a high-affinity anti-LPS antibody response. When compared retrospectively with the rate in a group of age- and gender-matched, nonimmunized, noncolonized patients with CF, the rate at which P. aeruginosa infections were acquired was significantly lower (p < or = 0.02) among all immunized versus nonimmunized patients during the first 2 years of observation. Subsequently, only those immunized patients who maintained a high-affinity anti-LPS antibody response had a significant reduction (p < or = 0.014) in the rate of infection during years 3 and 4. Smooth, typeable strains of P. aeruginosa predominated among immunized patients; rough, nontypeable strains were most frequently isolated from nonimmunized patients. Mucoid variants were isolated from one immunized patient versus six nonimmunized patients. These results indicate that the induction of a high-affinity P. aeruginosa anti-LPS antibody response can influence the rate of infection in patients with CF.

Mycobacterium genavense invasive infection in two children with AIDS: long-term followup.

Mycobacterium genavense is a rare cause of opportunistic infection in immunocompromised hosts. Follow up of two cases of M. genavense invasive infection in children with haemophilia A and AIDS are presented. One patient died 18 months after diagnosis of M. genavense infection of an indirectly related cause, probably of Pneumocystis carinii pneumonia. The second patient still attends our outpatient clinic and the infection is under control. Both presented with abdominal lymphomas and pain and a wasting syndrome. A combination of several drugs against atypical mycobacteria is used for treatment.

[Congenital toxoplasmosis: pediatric approach. Consensus report of the Swiss infectious disease pediatricians]. / Toxoplasmose congénitale: prise en charge pédiatrique. Texte de consensus des pédiatres infectiologues suisses.

The first part of this paper reviews: (1) the spectrum of clinical features of congenital toxoplasmosis; (2) the natural course of fetal infection; (3) the influence of antitoxoplasma therapy on the course of the disease; (4) methods for diagnosing the toxoplasma infection and assessing the severity of the disease; (5) currently used antitoxoplasma drugs and different therapeutic regimens. The second part suggests a practical approach to the problem of congenital toxoplasma infection, including diagnostic work-up, drug therapy, and follow-up. This practical approach is modulated according to the clinical syndrome in the infant and diagnostic and therapeutic considerations in the mother.

Use of the new quinolones in pediatrics.

For many years quinolone-induced cartilage toxicity observed in experiments with some skeletally immature animals represented indisputable contraindication for the use of these promising antimicrobials in prepubertal patients. Our clinical, magnetic resonance imaging and histopathological monitoring of ciprofloxacin use, together with the published experiences of other groups, suggest that the quinolone antibiotics do not cause arthropathy in humans. Conditions that potentially qualify for quinolone use (especially ciprofloxacin) in children include oral antipseudomonal (or antistaphylococcal) therapy for pulmonary exacerbation in cystic fibrosis, and for complicated urinary tract, skeletal, aural and shunt infections. In addition to these rare indications, there is an urgent need in developing countries for availability of the new quinolones for treating children with endemic and epidemic shigellosis and invasive salmonellosis. At present these compounds are not approved for pediatric patients; therefore each such treatment must be part of a controlled study or respect the compassionate use regularities.

Immunization of noncolonized cystic fibrosis patients against Pseudomonas aeruginosa.

The long-term safety and immunogenicity of a polyvalent Pseudomonas aeruginosa conjugate vaccine was evaluated in 30 noncolonized cystic fibrosis patients. Four doses were administered over 3 years, and patients were followed for a mean of 38 months. No acute or long-term adverse effects were noted. Immunization engendered a significant antibody response to all vaccine components. A decline in titers during year 3 of observation was associated with a marked rise in the isolation of P. aeruginosa. This organism was isolated repeatedly from the respiratory tract of 4 patients and only once from 7 patients. The remaining patients were repeatedly culture-negative. Only 1 patient showed clinical deterioration associated with multiple isolations of P. aeruginosa.

Use of the quinolones in paediatrics.

For many years, quinolone-induced cartilage toxicity observed in experiments involving immature animals has represented an indisputable contraindication for the use of these promising antimicrobials in prepubertal patients. Clinical, magnetic resonance imaging and histopathological monitoring of patients receiving ciprofloxacin at the University of Berne, together with published data, suggest that the quinolones do not cause arthropathy in humans. Conditions that potentially qualify for quinolone use (especially ciprofloxacin) in children include oral antipseudomonal (or antistaphylococcal) therapy for pulmonary exacerbations in cystic fibrosis, and complicated urinary tract, skeletal, aural and shunt infections. In addition to these rarer indications, there is an urgent need for the quinolones in developing countries for children with endemic and epidemic shigellosis and invasive salmonellosis. At present, these compounds are not approved for paediatric use and therefore must be administered as part of a controlled study or on a compassionate use basis in individual patients.

Affinity constants of naturally acquired and vaccine-induced anti-Pseudomonas aeruginosa antibodies in healthy adults and cystic fibrosis patients.

Naturally acquired anti-Pseudomonas aeruginosa antibody fails to afford protection against repeated P. aeruginosa bronchopulmonary exacerbations in cystic fibrosis (CF) patients. In an effort to explain this phenomenon, the titer and affinity constants of serum anti-lipopolysaccharide (LPS) IgG were determined in five study groups: healthy adults before and after immunization with a polyvalent LPS-based vaccine, healthy noncolonized CF patients before and after immunization, nonimmunized CF patients with significantly elevated anti-LPS antibody titers without documented colonization, recently colonized CF patients before and after immunization, and nonimmunized CF patients chronically colonized with P. aeruginosa. Immunization elicited a significant rise in total anti-LPS immunoglobulin levels and affinity constants in both healthy adults and CF patients. Although chronically colonized patients had elevated levels of total anti-LPS antibody, these antibodies possessed affinities at least 100-fold less than those of vaccine-induced antibodies.

[Assessment of the nephrotoxicity of amikacin in patients with cystic fibrosis]. / Untersuchung der Nephrotoxizität von Amikacin bei Patienten mit zystischer Fibrose.

Cystic fibrosis patients are at risk for nephrotoxic effects of aminoglycosides. Fifteen cystic fibrosis patients were admitted to hospital with 18 acute exacerbations of pulmonary symptoms associated with the isolation of Pseudomonas aeruginosa from sputum. They were treated intravenously with amikacin and ceftazidime for 14 days. Urinary excretion of N-acetyl-beta-D-glucosaminidase and alpha 1-microglobulin, two markers of tubular damage, and of albumin, a marker of glomerular permeability, was studied before and during treatment. Urinary activity of N-acetyl-beta-D-glucosaminidase and excretion of alpha 1-microglobulin was normal before amikacin treatment in approximately two thirds of patients and pathologically increased at the end of the study in 95%. Urinary albumin excretion was always normal before amikacin treatment and failed to increase consistently during treatment. The pattern of urinary protein excretion observed in the study before and during treatment with amikacin indicates a selective tubular toxicity.

Safety and immunogenicity of Pseudomonas aeruginosa conjugate A vaccine in cystic fibrosis.

To assess the safety and immunogenicity of a Pseudomonas aeruginosa octavalent O-polysaccharide-toxin A conjugate vaccine, 22 patients (mean age 7 years) with cystic fibrosis who had no history of colonisation with P aeruginosa were immunised with the vaccine. Adverse reactions were mild and self-limiting. IgG antibody concentrations to all vaccine antigens were significantly raised after vaccination and remained so for 12 months. Immunisation produced opsonic and toxin A neutralising antibodies. A booster dose given at 12 months led to an anamnestic response. There was no significant change in clinical status after vaccination. Further work to assess efficacy in patients with cystic fibrosis can now be considered since our findings support the safety and immunogenicity of the vaccine.

Clinical, radiologic and magnetic resonance monitoring for skeletal toxicity in pediatric patients with cystic fibrosis receiving a three-month course of ciprofloxacin.

Because of arthropathic toxicity observed in growing animals the quinolone antibiotics are not recommended for use in children. Recently, magnetic resonance imaging performed in juvenile animals was found to predict ciprofloxacin-induced cartilage damage at the knee joint. We conducted clinical, laboratory, radiologic and magnetic resonance imaging investigations in 13 prepubertal (age range, 6 to 13 years) and 5 postpubertal patients (age range, 14 to 24 years) with cystic fibrosis at the start and the end of a 3-month course of ciprofloxacin (30 mg/kg of body weight/day, administered orally in two equal doses) and at follow-up 4 to 6 months later. Our comprehensive monitoring gave no evidence for arthropathogenicity. Detailed physical skeletal function tests, height velocity values, laboratory studies of bone metabolism and conventional radiographs of both knees revealed no abnormalities. Moreover the serial magnetic resonance images of the left knee demonstrated lack of joint effusion, intact two-layer appearance of the cartilage and unaffected thickness of the articular cartilage measured at five anatomically different points. Our results together with the published data on quinolone use in pediatrics suggest that ciprofloxacin does not cause arthropathy in humans.