Tumor necrosis factor alpha/cachectin and interleukin 1 beta initiate meningeal inflammation.

Although previous studies using human cytokines in rabbits and rats have provided evidence of the participation of tumor necrosis factor alpha (TNF-alpha) and interleukin 1 beta (IL-1 beta) in the meningeal inflammatory cascade, the results obtained by several groups of investigators have been discordant or, at times, contradictory. In the present study, homologous cytokines were applied to the rabbit meningitis model. Intracisternal administration of 10(2)-10(5) IU of purified rabbit TNF-alpha (RaTNF-alpha) produced significant cerebrospinal fluid (CSF) inflammation. A similar response was observed after intracisternal inoculation of 5-200 ng of rabbit recombinant IL-1 beta (rrIL-1 beta). Preincubation of these two mediators with their specific antibodies resulted in an almost complete suppression of the CSF inflammatory response. In animals with Haemophilus influenzae type b lipooligosaccharide-induced meningitis, intracisternal administration of anti-rrIL-1 beta, anti-RaTNF-alpha, or both resulted in a significant modulation of meningeal inflammation. Simultaneous administration of 10(3) IU of RaTNF-alpha and 5 ng of rrIL-1 beta resulted in a synergistic inflammatory response manifested by a more rapid and significantly increased influx of white blood cells into the CSF compared with results after each cytokine given alone. These data provide evidence for a seminal role of TNF-alpha and IL-1 beta in the initial events of meningeal inflammation.

Tigecycline therapy significantly reduces the concentrations of inflammatory pulmonary cytokines and chemokines in a murine model of Mycoplasma pneumoniae pneumonia.

Mycoplasma pneumoniae is one of the causative agents of atypical community-acquired pneumonia. Tigecycline belongs to a new class of glycylcycline antimicrobials that have activity against a wide range of microorganisms, including in vitro activity against M. pneumoniae. We investigated the effect of tigecycline on microbiologic, histologic, and immunologic indices in a murine model of M. pneumoniae pneumonia. BALB/c mice were inoculated intranasally with M. pneumoniae and treated subcutaneously with tigecycline or placebo for 6 days. Outcome variables included quantitative bronchoalveolar lavage (BAL) M. pneumoniae culture, lung histopathologic score (HPS), BAL cytokine and chemokine concentrations (tumor necrosis factor alpha [TNF-alpha], gamma interferon [IFN-gamma], interleukin 1beta [IL-1beta], IL-2, IL-4, IL-5, IL-6, IL-10, IL-12 [p40/p70], granulocyte-macrophage colony-stimulating factor, MIP-1alpha, MIG, KC, MCP-1, and IP-10). BAL M. pneumoniae concentrations in mice treated with tigecycline (MpTige) tended to be reduced compared with mice treated with placebo (MpPl); however this did not reach statistical significance. The lung HPS was significantly lower, as well as the parenchymal-pneumonia subscore, in the MpTige mice than in the MpPl mice. MpTige mice had significantly lower BAL cytokine concentrations of IL-1beta, IL-12 (p40/p70), IFN-gamma, and TNF-alpha; of the chemokines, MIG, MIP-1alpha, and IP-10 were statistically lower in MpTige mice. While tigecycline treatment demonstrated a modest microbiologic effect, it significantly improved lung histologic inflammation and reduced pulmonary cytokines and chemokines.

Temperature-dependent modulation of lipopolysaccharide-induced interleukin-1 beta and tumor necrosis factor alpha expression in cultured human astroglial cells by dexamethasone and indomethacin.

In bacterial meningitis, LPS induces production in cerebrospinal fluid of the cytokines IL-1 beta and tumor necrosis factor alpha (TNF alpha), which are the principle mediators of meningeal inflammation. IL-1 beta and TNF alpha induce fever, and elevated temperature may affect cytokine expression. Dexamethasone treatment improves outcome in bacterial meningitis possibly by inhibiting IL-1 beta and TNF alpha. In this report, the effects of elevated temperature and dexamethasone on LPS-stimulated IL-1 beta and TNF alpha mRNA gene expression and protein synthesis were studied in human astrocytoma cell lines and primary cultures of human fetal astrocytes. Cells cultured at 40 degrees C exhibited smaller peaks of IL-1 beta and TNF alpha transcription and protein synthesis compared with cells cultured at 37 degrees C. The addition of dexamethasone before, during, or after exposure of the cells to LPS resulted in temperature-dependent inhibition of IL-1 beta transcription and protein synthesis. The most extensive inhibition occurred in pretreated cells cultured at 37 degrees C. Cotreatment with LPS and dexamethasone also inhibited TNF alpha mRNA transcription at both temperatures. The effects of another antiinflammatory agent, indomethacin, on LPS induction of IL-1 beta and TNF alpha mRNA were temperature and cell line dependent. These findings provide a possible explanation for the efficacy of dexamethasone treatment of bacterial meningitis and support the proposal that fever may be beneficial to the host in this disease.

Tumor necrosis factor in mediating experimental Haemophilus influenzae type B meningitis.

Tumor necrosis factor (TNF) could possibly be instrumental in mediating injury to the CNS during bacterial meningitis. In CSF of rabbits with meningitis induced with Haemophilus influenzae type b (Hib) lipooligosaccharide (LOS), TNF activity was first detected 45 min after intracisternal (IC) injection of 20 ng Hib LOS and white blood cells (WBC) first appeared 75 min later. The peak TNF activity (45 ng/ml) was observed at 120 min after IC and persisted for 5 h. When 1-2 X 10(7) CFU of Hib was used to induce meningitis, peak CSF TNF activity was comparable with that after 20 ng Hib LOS, but the activity persisted for 14 h. Dexamethasone (DXM) (1 mg/kg per i.v.) given 1 h before or simultaneously with IC Hib LOS reduced significantly TNF activity and meningeal inflammation. Goat anti-human TNF alpha antibodies given IC with 20 ng Hib LOS or 2 X 10(6) CFU of Hib resulted in a significant reduction in CSF TNF concentrations, which was also associated with reduced meningeal inflammation in Hib LOS-inoculated animals. We conclude that TNF participates in mediating meningeal inflammation associated with Hib experimental meningitis, and that DXM, when given before or with Hib LOS, inhibits CSF TNF production and modulates the meningeal inflammatory response.

Enhanced attenuation of meningeal inflammation and brain edema by concomitant administration of anti-CD18 monoclonal antibodies and dexamethasone in experimental Haemophilus meningitis.

Antiinflammatory therapy has been shown to reduce the adverse pathophysiological consequences that occur in bacterial meningitis and to improve outcome from disease. In the present study, modulation of two principal steps of the meningeal inflammatory cascade was accomplished by concomitant administration of dexamethasone to diminish overproduction of cytokines in response to a bacterial stimulus and of a monoclonal antibody directed against adhesion-promoting receptors on leukocytes to inhibit recruitment of white blood cells into the subarachnoid space. Dexamethasone and antibody therapy produced a marked attenuation of all indices of meningeal inflammation and reduction of brain water accumulation after H. influenzae-induced meningitis in rabbits compared with results of each agent given alone and of untreated animals. In addition, the enhanced host's meningeal inflammatory reaction that follows antibiotic-induced bacterial lysis was profoundly ameliorated when dual therapy was administered without affecting clearance rates of bacteria from cerebrospinal fluid and vascular compartments. The combination of both therapeutic approaches may offer a promising mode of treatment to improve further the outcome from bacterial meningitis.

Specific detection of Haemophilus influenzae type b lipooligosaccharide by a polymyxin B monoclonal antibody assay.

A monoclonal antibody (MAb)-based enzyme immunoassay was developed for detection of Haemophilus influenzae type b (Hib) lipooligosaccharides (LOS). The high affinity of polymyxin B for lipid A was used to bind the Hib LOS to microtiter wells. The immobilized LOS was detected with MAbs directed against the oligosaccharide component of Hib endotoxin. Hib LOS concentrations were measured in in vitro samples and in cerebrospinal fluid (CSF) sample obtained from rabbits with experimental Hib meningitis. The sensitivity of the assay was 1 ng LOS/ml sample and the results obtained with this assay correlated significantly with those obtained with the standard Limulus amebocyte lysate assay. This new assay provides a method for specific detection of Hib LOS in CSF samples and in aqueous laboratory fluids. This general methodology should also be useful for experimental research involving specific LPS/LOS molecules.

Management of bacterial meningitis in infants and children. Current status and future prospects.

Outcome from bacterial meningitis in infants and children has not appreciably changed in a 14-year period from 1969 to 1982 at Children's Medical Center and Parkland Memorial Hospital, Dallas, Texas. Overall, the case-fatality rate was 6.4 percent; it was 4.6 percent for 414 patients managed in 1969 to 1972 and 3.9% for 376 patients in 1981 and 1982. In neonatal meningitis due to group B streptococci or coliform bacilli, the fatality rates were comparable in 1969 to 1972 and 1981 and 1982; ampicillin and an aminoglycoside were the mainstays of therapy during these periods. Because of changing susceptibilities of gram-negative enteric bacilli to the aminoglycosidic agents, Haemophilus influenzae to ampicillin and possibly chloramphenicol and of Streptococcus pneumoniae to penicillin, alternatives to conventional therapy must be developed and thoroughly tested. Assessment of new antimicrobial agents in the rabbit model of experimental meningitis provides valuable information on penetration of drug into cerebrospinal fluid, on achievable bactericidal activity in spinal fluid and on the bacteriologic effect of single dose or nine hour infusion therapy. These data are directly applicable to therapy in infants and children with meningitis. Although newer antimicrobial agents such as moxalactam, cefotaxime, or ceftriaxone have greatly enhanced bactericidal activity against the commonly encountered pathogens, outcome from meningitis will not be substantially improved with therapy using these agents. Improved outcome will more likely occur with the advent of therapeutic modalities that prevent or rapidly decrease cerebral edema and cerebritis, thereby preserving cerebral perfusion pressure and cellular integrity.

Aminoglycoside toxicity in infants and children.

The aminoglycosides are frequently prescribed for infants and children, especially newborn infants with suspected or documented sepsis or meningitis. In older infants and children, the aminoglycosides are commonly used to treat acute respiratory exacerbations in patients with cystic fibrosis, intra-abdominal sepsis, complicated urinary tract infections, and other infections caused by gram-negative enteric bacilli. Although these drugs are generally well tolerated and efficacious, there is relatively little information on toxicity in pediatric patients. The potential for ototoxicity from the aminoglycosides, especially streptomycin, kanamycin, and gentamicin, was evaluated in seven prospective, controlled studies of 1,321 newborn infants. Although the designs and follow-up periods were different among the studies, the audiometric tests were similar and appropriate for age. Three studies measured auditory brain stem response during the neonatal and early infancy periods. With the exception of one study, ototoxicity occurred less frequently in aminoglycoside-treated patients than it did in untreated control patients. One study from Canada demonstrated abnormal brain stem response audiograms in gentamicin- or tobramycin-treated neonates compared with normal brain stem response audiograms in untreated control subjects. That study, however, was flawed by the small number of patients evaluated and the lack of follow-up of any patients. Nephrotoxicity appears to be rare in neonates, although one study in this age group showed an elevated N-acetyl-beta-glucosaminidase excretion rate in gentamicin-treated infants compared with rates in infants treated with amikacin or chloramphenicol. In that study, no attempt was made to correlate lysosomal injury with clinical or conventional laboratory evidence of nephrotoxicity. The toxicity of the aminoglycosides in older infants and children has not been adequately assessed. The broadest experience with these compounds has been in patients with cystic fibrosis, and most open studies in these patients have indicated a relative lack of ototoxicity and nephrotoxicity. It should be emphasized, however, that the standard dosage of aminoglycosides in patients with cystic fibrosis frequently results in serum concentrations that are lower than anticipated because of a relatively larger volume of drug distribution and a greater urinary excretion rate. The lack of reports on aminoglycoside-associated toxic effects in children suggests that these compounds are safe and well tolerated in this age group.

Delayed cerebrospinal fluid sterilization and adverse outcome of bacterial meningitis in infants and children.

To determine the clinical importance of CSF cultures that are persistently positive for pathogens in patients treated for meningitis with the new cephalosporins, the records of 301 infants and children with bacterial meningitis enrolled prospectively in four clinical efficacy trials of cefuroxime or ceftriaxone therapy were reviewed. CSF culture results were positive for 20 patients and they were sterile at 18 to 36 hours after start of therapy for 281 patients. Seizures, subdural effusions, and hemiparesis were found significantly more often during hospitalization in those with delayed sterilization of CSF. Children with persistently positive cultures had a significantly higher incidence of neurologic abnormalities at the time of hospital discharge (45% v 19%) and at follow-up (41% v 13%) and of moderate to profound hearing impairment (35% v 15%) than did those with prompt sterilization of CSF. Repeat CSF examination is a useful prognostic indicator in infants and young children with bacterial meningitis.

Urinary tract infections in young infants.

The clinical and laboratory features of urinary tract infections in 100 infants aged 5 days to 8 months are presented. Of the patients in the first three months of life 75% were boys, and of infants aged 3 to 8 months only 11% were boys; 95% of the infants were uncircumcised. Sepsis was documented in 31% of neonates, 21% of infants aged 1 to 2 months, 14% of those aged 2 to 3 months, and 5.5% of infants greater than 3 months of age. Roentgenographic abnormalities of the urinary system were found in 45% of female and 7% of male infants. All infants responded promptly to antimicrobial therapy. The possible factors related to the predominance of male infants with urinary tract infections in the first three months of life are discussed.

Intravenous administration of kanamycin and gentamicin in newborn infants.

The pharmacokinetics of kanamycin and gentamicin were studied after intramuscular (IM) and intravenous (IV) (constant infusion over 20 minutes) administration in newborn infants. The serum concentrations, half-lives, area-under-the-curve values, and volumes of distribution were similar for each drug after both routes of administration. Based on these pharmacological similarities, it is likely that these aminoglycosides can be given safely and effectively as constant IV infusions to neonates in whom IM injections are not feasible.

Streptococcal submandibular cellulitis in young infants.

Six infants with streptococcal submandibular cellulitis and bacteremia were managed in our institution during a seven-month period. Five uncomplicated cases were caused by group B beta-hemolytic Streptococcus, and one rapidly progressive case of Ludwig's angina was caused by group A Streptococcus. Recognition of this characteristic clinical presentation of group B streptococcal infection may be beneficial in the management of such patients.

Serum penicillin concentrations after intramuscular administration of benzathine penicillin G in children.

Concentrations of penicillin were measured in serum samples of 26 children who received benzathine penicillin G (BPG) alone or in combination with procaine penicillin (PBPG). Both preparations were well absorbed; peak concentrations of penicillin after PBPG administration were 25-fold larger than those after BPG. One third and one half of serum samples from BPG and PBPG patients, respectively, contained no measurable penicillin activity at 18 days. At 30 days, there was no penicillin activity in any of the samples. These data raise questions regarding the use of BPG and PBPG for prophylaxis of group A streptococcal and pneumococcal infections.

Pharmacokinetics of rifampin in infants and children: relevance to prophylaxis against Haemophilus influenzae type b disease.

Pharmacokinetic studies of rifampin were performed in 38 infants and children after administration of three different oral formulations. Mean peak serum concentrations of from 9 to 11.5 microgram/ml were observed one hour after a 10-mg/kg dose and the average half-life was 2.9 hours. Patients who received rifampin suspension in applesauce had smaller serum concentrations and area-under-the-curve values than did those who were given suspension alone. The mixture of rifampin powder and applesauce resulted in more variable serum levels. The concentrations of drug in tears from 18 subjects were similar to those in serum. All but one of 118 saliva specimens obtained from two to eight hours after the 10-mg/kg dose had antimicrobial activity. Of samples taken at two hours, 95% contained rifampin levels that exceeded the minimal bacterial concentration for 15 Haemophilus influenzae type b strains. Bactericidal activity against Haemophilus correlated with salivary rifampin concentrations and was detectable in virtually all specimens containing greater than or equal to 0.8 microgram/ml. These data provide the pharmacokinetic basis for rifampin prophylaxis of close contacts of H influenza type b disease, but are insufficient alone to recommend routine usage of rifampin for this purpose until results of additional epidemiologic studies are available.

Evaluation of short-term antibiotic therapy in children with uncomplicated urinary tract infections.

This study was designed to determine whether serum C-reactive protein (CRP) concentrations could be used to identify children with uncomplicated lower urinary tract infection who would respond favorably to short-term antibiotic therapy. A one-day or ten-day regimen of cefadroxil (30 mg/kg/day in two divided doses) was assigned randomly to 80 children who had acute urinary tract infection and CRP concentrations less than 28 microgram/ml (CRP-negative group). Ten days of cefadroxil therapy was used to treat 44 children with urinary tract infection and CRP values greater than or equal to 28 microgram/ml (CRP-positive group). The clinical and laboratory characteristics of the children in the two CRP-negative therapy groups were similar to, but different from those of children with CRP-positive infections. Recurrent infections occurred significantly more often at four to five days after completion of therapy in CRP-negative children who received one day (44.4%) compared to ten days (20%) of cefadroxil therapy (P less than .05). When data from this study were combined with those from our previously published investigation of short-term antibiotic therapy in CRP-negative children, a significantly larger percentage of recurrences was documented immediately after one or four days of antibiotics (79%) compared to recurrences after the standard ten-day regimen (41%). Additionally, the total rate of recurrent infections for all children in both studies was significantly larger in those who received short-term therapy (48%) as opposed to conventional therapy (34%). These data indicate that short-term antibiotic therapy is less effective than the conventional ten-day regimen in children with CRP-negative urinary tract infection.

Pyogenic arthritis of the sacroiliac joint in pediatric patients.

Clinical manifestations, diagnostic studies, and management of pyogenic sacroiliitis were reviewed in 77 pediatric patients. This infection occurs primarily in late childhood, is more common in boys, and has a subacute onset in about two thirds of cases. Recognition of the characteristic signs and symptoms of sacroiliac involvement coupled with radioisotope bone scanning substantially reduces the delay in correct diagnosis that averaged 3.9 weeks in all patients (4.8 weeks in those without and 1.7 weeks in those with bone scans performed). Joint aspiration under biplane fluoroscopic control and culture of the aspirated material is indicated in establishing the specific etiologic agent which is Staphylococcus aureus in most cases. Adequate management of pyogenic sacroiliitis consists of appropriately monitored antibiotic treatment and, if present, evacuation of pus. The use of spica cast immobilization offers no apparent beneficial effect. Indications for surgery include drainage of pus and removal of sequestered bone. With adequate management the prognosis of suppurative sacroiliitis in pediatric patients is excellent, despite persistent abnormal radiographic findings in most patients.

Comparative pharmacokinetics of amoxicillin and ampicillin in infants and children.

The pharmacokinetics of amoxicillin and ampicillin were studied in 24 infants and children. Mean peak serum concentrations of 5.4 micrograms/ml in fasting and 3.2 micrograms/ml in nonfasting patients were observed after 15 mg/kg amoxicillin doses. Area under the curve values and serum half-life values were similar in fasting and nonfasting patients. The pharmacokinetics of amoxicillin (15 mg/kg) were compared to those of ampicillin (25 mg/kg). Peak serum concentrations, area under the curve values and half-life times were comparable for the two drugs. Amoxicillin (25 mg/kg) and ampicillin (25 mg/kg) were compared in cross-over fashion in 11 children. Serum concentrations of amoxicillin were consistently larger than those of ampicillin; the differences were of borderline significance at one and two hours and statistically significant at four and six hours after the dosage. The bioavailability of amoxicillin was twice that of ampicillin. Amoxicillin was detected in approximately half of the saliva samples studied. Although the salivary concentrations in many children exceeded the inhibitory level for most pneumococci and group A streptococci and for many non-beta lactamase-producing Haemophilus influenzae type b strains, the clinical relevance of these observations is unknown.

Recrudescence and relapse in bacterial meningitis of childhood.

Antibiotic therapy of bacterial meningitis in children may be complicated by reappearance of bacteria in cerebrospinal fluid during therapy (recrudescence) or within three weeks after therapy is stopped (relapse). Clinical and laboratory features of six children with recrudescence and of 21 children with relapse were reviewed. These complications occurred mainly in infants less than 2 years of age and comprised less than 1% of all cases of bacterial meningitis. Neither the initial nor the follow-up CSF findings were predictive of recrudescence or relapse. Prolonged or secondary fever was unrelated to these complications. Recrudescence was usually caused by inappropriate therapy whereas relapse after adequate therapy of bacterial meningitis was usually ascribed to persistence of infection in meningeal or parameningeal foci. Relapse did not become manifest until three or more days after discontinuation of therapy. It is concluded that routine examination of CSF at the end of adequate anti-microbial therapy is not necessary or useful when the patient has exhibited a satisfactory clinical response. Furthermore, the commonly recommended observation period of 48 hours in the hospital after discontinuation of therapy is not justified for a patient who has had an uneventful course.

Osteoarticular infections in children with sickle cell disease.

Thirteen children with sickle cell disease were identified as having 14 episodes of osteoarticular infection in a review of 27 years' experience. There were eight episodes of osteomyelitis or osteoarthritis and six of suppurative arthritis alone. The etiologic agents in osteomyelitis or osteoarthritis were Salmonella sp in four cases, Escherichia coli in one, Enterobacter aerogenes in one, Staphylococcus aureus in one, and Haemophilus influenzae type b in one. Five of the cases with infection limited to the joint were caused by Streptococcus pneumoniae; the sixth was caused by H influenzae type b. Fever (greater than or equal to 38.3 degrees C) was present in all children and the temperature was in excess of 39 degrees C in 62%. The mean duration of pain before admission was 4.5 days. The initial total white blood cell count ranged from 5,200 to 29,700/microL (mean 19,436/microL) and the total band neutrophil count ranged from 0 to 5,103/microL (mean 1,660/microL). The ESR was greater than 20 mm/h in eight of the ten patients who were tested. Management consisted of antibiotic therapy in all. Needle aspiration was performed in two patients with osteomyelitis and in three with suppurative arthritis. Incision and drainage was performed in two cases of osteomyelitis and in four with suppurative arthritis. The outcome was satisfactory in all except one patient who had several complications as a consequence of femoral neck osteomyelitis. Recurrence was reported in only one patient.

Pharmacologic evaluation of orally administered antibiotics in infants and children: effect of feeding on bioavailability.

The clinical pharmacology of orally administered antibiotics was investigated in 106 infants and children. The antibiotic suspensions studied were ampicillin, cephalexin, erythromycin estolate, erythromycin ethylsuccinate, penicillin G, and penicillin V. The feeding status of the patients was evaluated in relation to the concentrations of drugs in serum, saliva, and tears. Peak concentrations and area-under-the-curve values of cephalexin, penicillin V, and penicillin G were reduced 40% to 60% in patients given milk and drug concurrently. Absorption was enhanced when erythromycin ethylsuccinate was given milk. After administration of both erythromycin formulations, penicillin V and ampicillin, salivary concentrations exceeded the minimal inhibitory concentrations for most pneumococci and group A streptococci and for many meningococci. The clinical implications of these pharmacokinetic data are discussed.