Susanne Suter

A Comparison of Ceftriaxone and Cefuroxime for the Treatment of Bacterial Meningitis in Children

To compare ceftriaxone with cefuroxime for the treatment of meningitis, we conducted a study in which 106 children with acute bacterial meningitis were randomly assigned to receive either ceftriaxone (100 mg per kilogram of body weight per day, administered intravenously once daily; n = 53) or cefuroxime (240 mg per kilogram per day, administered intravenously in four equal doses; n = 53). The mean age of the children was 3 years (range, 42 days to 16 years), and the characteristics of the two treatment groups were comparable at admission. Excluded from the study were eight other children who died within 48 hours of admission. After 18 to 36 hours of therapy, cultures of cerebrospinal fluid remained positive for 1 of the 52 children (2 percent) receiving ceftriaxone for whom cultures were available and 6 of 52 (12 percent) receiving cefuroxime (P = 0.11). In both groups the mean duration of antibiotic therapy was 10 days. The clinical responses to therapy were similar in the two treatment groups, and all 106 children were cured. Reversible biliary pseudolithiasis was detected by serial abdominal ultrasonography only in the children treated with ceftriaxone (16 of 35 vs. 0 of 35; P less than 0.001). The treatment of three children was switched from ceftriaxone to alternative antibiotics because these children had upper abdominal pain. Other side effects were infrequent in both groups. At follow-up examination two months later, moderate-to-profound hearing loss was present in two children (4 percent) treated with ceftriaxone and in nine (17 percent) treated with cefuroxime (P = 0.05); other neurologic abnormalities were similar in the two treatment groups. We conclude that ceftriaxone is superior to cefuroxime for the treatment of acute bacterial meningitis in children and that the benefits of milder hearing impairment and more rapid sterilization of the cerebrospinal fluid with ceftriaxone outweigh the problem of reversible biliary pseudolithiasis with this drug.

Procalcitonin, IL-6, IL-8, IL-1 receptor antagonist and C-reactive protein as identificators of serious bacterial infections in children with fever without localising signs

Abstract Fever without localising signs in very young children remains a diagnostic problem. Until present, a clinical scoring system combined with leucocyte count, urine analysis and determination of CRP are recognised as being helpful to identify patients at risk of serious bacterial illness. In this study we asked the question whether the determination of procalcitonin (PCT), interleukin (IL)-6, IL-8 and interleukin-1 receptor antagonist (IL-1Ra) was superior to these commonly used markers for the prediction of a serious bacterial infection (SBI). Children, 7 days to 36 months of age, with a rectal temperature above 38 °C and without localising signs of infection were prospectively enrolled. For each infant, we performed a physical examination, a clinical score according to McCarthy, a complete white cell count, an urine analysis and a determination of CRP. We further determined PCT, IL-6, IL-8, and IL-1Ra concentrations and compared their predictive value with those of the usual management of fever without localising signs. Each infant at risk of SBI had blood culture, urine and cerebrospinal fluid cultures when indicated, and received antibiotics until culture results were available. A total of 124 children were included of whom 28 (23%) had SBI. Concentrations of PCT, CRP and IL-6 were significantly higher in the group of children with SBI but IL-8 and IL-1Ra were comparable between both groups. PCT showed a sensitivity of 93% and a specificity of 78% for detection of SBI and CRP had a sensitivity of 89% and a specificity of 75%. Conclusion Compared to commonly used screening methods such as the McCarthy score, leucocyte count and other inflammatory markers such as interleukin-6, interleukin-8 and interleukin-1 receptor antagonist, procalcitonin and C-reactive protein offer a better sensitivity and specificity in predicting serious bacterial infection in children with fever without localising signs.

Usefulness of procalcitonin and C-reactive protein rapid tests for the management of children with urinary tract infection

BACKGROUND Urinary tract infection (UTI) is a common problem in children. Because clinical findings and commonly used blood indices are nonspecific, the distinction between lower and upper urinary tract infection cannot be made easily in this population. However, this distinction is important because renal infection can induce parenchymal scarring. The objective of this study was to determine the accuracy of procalcitonin (PCT) compared with C-reactive protein (CRP) rapid tests to predict renal involvement in children with febrile UTI. METHODS PCT and CRP were measured in the blood of children admitted to the emergency room with fever, signs and symptoms of urinary tract infection and/or a positive urine dipstick analysis. Renal parenchymal involvement was assessed by a 99mTc-labeled dimercaptosuccinic acid renal scan in the acute phase of infection in all children. Sensitivity, specificity and likelihood ratios were determined for both tests. RESULTS Fifty-four children with a proven urinary tract infection were enrolled: 63% had renal involvement; and 37% had infection restricted to the lower urinary tract. No difference was found for age, sex and total white blood cell count between the groups. The calculated likelihood ratios of procalcitonin and C-reactive protein rapid tests were between 3.8 and 7 and 1.5 and 2.8, respectively. A positive PCT value predicted renal involvement in 87 to 92% of children with febrile UTI, compared with 44 to 83% using CRP values. CONCLUSIONS A rapid determination of procalcitonin concentration could be useful for the management of children with febrile UTI in the emergency room.

Efficacy of inhaled amikacin as adjunct to intravenous combination therapy (ceftazidime and amikacin) in cystic fibrosis.

Eighty-seven patients with cystic fibrosis were admitted to hospital with an acute exacerbation of pulmonary symptoms associated with isolation of Pseudomonas aeruginosa from sputum. The patients were randomly allocated to receive intravenously administered ceftazidime (250 mg/kg/day) and amikacin (33 mg/kg/day) alone or with inhaled amikacin (100 mg twice a day). Other aspects of the 2-week treatment were constant. The two therapy groups were comparable in all aspects. At the completion of therapy, the addition of aerosolized amikacin produced temporary eradication of P. aeruginosa in 70% of the patients, compared with 41% in the intravenous therapy only group (P less than 0.02). Suppression of P. aeruginosa in sputum cultures was correlated with the amikacin sputum concentrations. However, both regimens resulted in similar improvements in clinical, radiologic, laboratory, and pulmonary function measurements, and within 4 to 6 weeks most patients were recolonized with P. aeruginosa. There was no serious toxicity or adverse effect. In patients with cystic fibrosis, the addition of aerosol aminoglycoside to systemic antipseudomonal combination therapy is not clinically beneficial.

Regulation of gap junctional communication by a pro-inflammatory cytokine in cystic fibrosis transmembrane conductance regulator-expressing but not cystic fibrosis airway cells

Airway inflammation is orchestrated by cell-cell interactions involving soluble mediators and cell adhesion molecules. Alterations in the coordination of the multicellular process of inflammation may play a major role in the chronic lung disease state of cystic fibrosis (CF). The aim of this study was to determine whether direct cell-cell interactions via gap junctional communication is affected during the inflammatory response of the airway epithelium. We have examined the strength of intercellular communication and the activation of nuclear factor-kappaB (NF-kappaB) in normal (non-CF) and CF human airway cell lines stimulated with tumor necrosis factor-alpha (TNF-alpha). TNF-alpha induced maximal translocation of NF-kappaB into the nucleus of non-CF as well as CF airway cells within 20 minutes. In non-CF cells, TNF-alpha progressively decreased the extent of intercellular communication. In contrast, gap junctional communication between CF cells exposed to TNF-alpha remained unaltered. CF results from mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Interestingly, transfer of wild-type CFTR into CF cells by adenovirus-mediated infection was associated with the recovery of TNF-alpha-induced uncoupling. These results suggest that expression of functional CFTR is necessary for regulation of gap junctional communication by TNF-alpha. Gap junction channels close during the inflammatory response, therefore limiting the intercellular diffusion of signaling molecules, and thereby the recruitment of neighboring cells. Defects in this mechanism may contribute to the excessive inflammatory response of CF airway epithelium.

Serum tumour necrosis factor in newborns at risk for infections

Tumour necrosis factor-α (TNF-α) is an important mediator in the pathogenesis of Gram-negative shock. In order to assess the role of TNF-α as a marker of the severity of infections in the neonates, serum TNF-α concentrations were determined at the time of septic work-up in 69 newborns (gestational age: 28–40 weeks). Nine patients had systemic infection (group A), four of them with signs of circulatory failure. Eleven patients had positive cultures of gastric aspiration or placental smears (group B) and 49 patients had completly negative septic work-up. Patients of group A had significantly more elevated serum TNF-α levels than patients of group B and C. Within group A, patients with circulatory failure had mean serum TNF-α concentration of 2165±817 pg/ml versus 27±8 pg/ml in newborns without shock. Serum TNF-α concentrations of more than 15 pg/ml detected systemic infections in eight out of nine patients. The specificity was 98% (1 elevated TNF-α concentration out of 60 non infected patients). These data indicate that premature neonates and term newborns are able to produce TNF-α when they are infected. Highly elevated TNF-α concentrations are found in severe systemic infections causing cardiovascular impairment.

Defective regulation of gap junctional coupling in cystic fibrosis pancreatic duct cells.

The cystic fibrosis (CF) gene encodes a cAMP-gated Cl- channel (cystic fibrosis transmembrane conductance regulator [CFTR]) that mediates fluid transport across the luminal surfaces of a variety of epithelial cells. We have previously shown that gap junctional communication and Cl- secretion were concurrently regulated by cAMP in cells expressing CFTR. To determine whether intercellular communication and CFTR-dependent secretion are related, we have compared gap junctional coupling in a human pancreatic cell line harboring the DeltaF508 mutation in CFTR and in the same cell line in which the defect was corrected by transfection with wild-type CFTR. Both cell lines expressed connexin45 (Cx45), as evidenced by RT-PCR, immunocytochemistry, and dual patch-clamp recording. Exposure to agents that elevate intracellular cAMP or specifically activate protein kinase A evoked Cl- currents and markedly increased junctional conductance of CFTR-expressing pairs, but not in the parental cells. The latter effect, which was caused by an increase in single-channel activity but not in unitary conductance of Cx45 channels, was not prevented by exposing CFTR-expressing cells to a Cl- channel blocker. We conclude that expression of functional CFTR restored the cAMP-dependent regulation of junctional conductance in CF cells. Direct intercellular communication coordinates multicellular activity in tissues that are major targets of CF manifestations. Consequently, defective regulation of gap junction channels may contribute to the altered functions of tissues affected in CF.

Cystic Fibrosis Transmembrane Conductance Regulator Does Not Affect Neutrophil Migration across Cystic Fibrosis Airway Epithelial Monolayers

Recent studies have shown that airway inflammation dominated by neutrophils, ie, polymorphonuclear cells (PMN) was observed in infants and children with cystic fibrosis (CF) even in the absence of detectable infection. To assess whether there is a CF-related anomaly of PMN migration across airway epithelial cells, we developed an in vitro model of chemotactic migration across tight and polarized CF(15) cells, a CF human nasal epithelial cell line, seeded on porous filters. To compare PMN migration across a pair of CF and control monolayers in the physiological direction, inverted CF(15) cells were infected with increasing concentrations of recombinant adenoviruses containing either the normal cystic fibrosis transmembrane conductance regulator (CFTR) cDNA, the DeltaF508 CFTR cDNA, or the beta-galactosidase gene. The number of PMN migrating in response to N-formyl-Met-Leu-Phe across inverted CF(15) monolayers expressing beta-galactosidase was similar to that seen across CF(15) monolayers rescued with CFTR, whatever the proportion of cells expressing the transgene. Moreover, PMN migration across monolayers expressing various amounts of mutated CFTR was not different from that observed across matched counterparts expressing normal CFTR. Finally, PMN migration in response to adherent or Pseudomonas aeruginosa was equivalent across CF and corrected monolayers. The possibility that mutated CFTR may exert indirect effects on PMN recruitment, via an abnormal production of the chemotactic cytokine interleukin-8, was also explored. Apical and basolateral production of interleukin-8 by polarized CF cells expressing mutated CFTR was not different from that observed with rescued cells, either in baseline or stimulated conditions. CF(15) cells displayed a CF phenotype that could be corrected by CFTR-containing adenoviruses, because two known CF defects, Cl(-) secretion and increased P. aeruginosa adherence, were normalized after infection with those viruses. Thus, we conclude that the presence of a mutated CFTR does not per se lead to an exaggerated inflammatory response of CF surface epithelial cells in the absence or presence of a bacterial infection.

Modulation of Pancreatic Acinar Cell to Cell Coupling during ACh-evoked Changes in Cytosolic Ca2+

The temporal changes in cytosolic free Ca2+ ([Ca2+] i ), Ca2+-dependent membrane currents (Im ), and gap junctional current (Ij ) elicited by acetylcholine (ACh) were measured in rat pancreatic acinar cells using digital imaging and dual perforated patch-clamp recording. ACh (50 nm-5 μm) increased [Ca2+] i and evokedIm currents without alteringIj in 19 of 37 acinar cell pairs. Although [Ca2+] i rose asynchronously in cells comprising a cluster, the delay of the [Ca2+] i responses decreased with increasing ACh concentrations. Perfusion of inositol 1,4,5-trisphosphate (IP3) into one cell of a cluster resulted in [Ca2+] i responses in neighboring cells that were not necessarily in direct contact with the stimulated one. This suggests that extensive coupling between acinar cells provides a pathway for cell-to-cell diffusion of Ca2+-releasing signals. Strikingly, maximal (1–5 μm) ACh concentrations reduced Ij by 69 ± 15% (n = 9) in 25% of the cell pairs subjected to dual patch-clamping. This decrease occurred shortly after the Im peak and was prevented by incubating acinar cells in a Ca2+-free medium, suggesting that uncoupling was subsequent to the initiation of the Ca2+-mobilizing responses. Depletion of Ca2+-sequestering stores by thapsigargin resulted in a reduction of intercellular communication similar to that observed with ACh. In addition, ACh-induced uncoupling was prevented by blocking nitric oxide production with l-nitro-arginine and restored by exposing acinar cells to dibutyryl cGMP. The results suggest that ACh-induced uncoupling and capacitative Ca2+ entry are regulated concurrently. Closure of gap junction channels may occur to functionally isolate nearby cells differing in their intrinsic sensitivity to ACh and thereby to allow for sustained activity of groups of secreting cells.

Bartonella quintana endocarditis in a child.

To the Editor: Blood-culture–negative endocarditis has been described in about 12 percent of children with endocarditis.1 Because of recent diagnostic advances, some of the pathogens responsible fo...