[Show abstract][Hide abstract] ABSTRACT: Clarithromycin is postulated to possess immunomodulatory properties in addition to its antimicrobial activity.
To evaluate the effect of clarithromycin on serum and nasopharyngeal cytokine and chemokine concentrations in children with an acute exacerbation of recurrent wheezing.
Children with a history of recurrent wheezing or asthma and who presented with an acute exacerbation of wheezing were enrolled in a double-blind, randomized trial of clarithromycin vs placebo. Concentrations of tumor necrosis factor alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-1beta (IL-1beta), IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, granulocyte-macrophage colony-stimulating factor, RANTES, eotaxin, macrophage inflammatory protein 1alpha, macrophage inflammatory protein 1beta, and monocyte chemoattractant protein 1 were measured in serum and/or nasopharyngeal aspirates before, during, and after therapy. Mycoplasma pneumoniae and Chlamydophila pneumoniae infection were evaluated for by polymerase chain reaction and serologic testing.
Nasopharyngeal concentrations of TNF-alpha, IL-1beta, and IL-10 were significantly and persistently lower in children treated with clarithromycin compared with placebo. There tended to be a greater effect of clarithromycin on nasopharyngeal cytokine concentrations in patients with evidence of M. pneumoniae or C. pneumoniae infection. No significant differences were detected in serum cytokines for children treated with clarithromycin compared with placebo.
Clarithromycin therapy reduces mucosal TNF-alpha, IL-1beta, and IL-10 concentrations in children with an acute exacerbation of recurrent wheezing.
Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology 11/2006; 97(4):457-63. DOI:10.1016/S1081-1206(10)60935-0 · 2.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Respiratory syncytial virus (RSV) is the leading viral pathogen responsible for bronchiolitis and pneumonia in infants and young children worldwide. We have previously shown in the mouse model that treatment with an anti-RSV neutralizing monoclonal antibody (MAb) against the F glycoprotein of RSV, palivizumab, decreased lung inflammation, airway obstruction, and postmethacholine airway hyperresponsiveness. MEDI-524, or Numax, is a new MAb derived from palivizumab with enhanced neutralizing activity against RSV. We compared the effects of these two MAbs on different markers of disease severity using the murine model of RSV infection. BALB/c mice were intranasally inoculated with RSV A2. Palivizumab or MEDI-524 was administered once at either 24 h before or 48 h after RSV inoculation. Regardless of the time of administration, all treated mice showed significantly decreased RSV loads in bronchoalveolar lavage samples measured by plaque assay. Only MEDI-524 given at -24 h significantly decreased lung RSV RNA loads on days 5 and 28 after RSV inoculation. Pulmonary histopathologic scores, airway obstruction, and postmethacholine airway hyperresponsiveness were significantly reduced in mice treated with MEDI-524 at 24 h before inoculation, compared with untreated controls and the other regimens evaluated. MEDI-524 was superior to palivizumab on several outcome variables of RSV disease assessed in the mouse model: viral replication, inflammatory and clinical markers of acute disease severity, and long-term pulmonary abnormalities.
[Show abstract][Hide abstract] ABSTRACT: Respiratory syncytial virus (RSV) is the leading respiratory viral pathogen in young children worldwide. RSV disease is associated with acute airway obstruction (AO), long-term airway hyperresponsiveness (AHR), and chronic lung inflammation. Using two different mouse strains, this study was designed to determine whether RSV disease patterns are host-dependent. C57BL/6 and BALB/c mice were inoculated with RSV and followed for 77 days. RSV loads were measured by plaque assay and polymerase chain reaction (PCR) in bronchoalveolar lavage (BAL) and whole lung samples; cytokines were measured in BAL samples. Lung inflammation was evaluated with a histopathologic score (HPS), and AO and AHR were determined by plethysmography.
Viral load dynamics, histopathologic score (HPS), cytokine concentrations, AO and long-term AHR were similar in both strains of RSV-infected mice, although RSV-infected C57BL/6 mice developed significantly greater AO compared with RSV-infected BALB/c mice on day 5. PCR detected RSV RNA in BAL samples of RSV infected mice until day 42, and in whole lung samples through day 77. BAL concentrations of cytokines TNF-alpha, IFN-gamma, and chemokines MIG, RANTES and MIP-1alpha were significantly elevated in both strains of RSV-infected mice compared with their respective controls. Viral load measured by PCR significantly correlated with disease severity on days 14 and 21.
RSV-induced acute and chronic airway disease is independent of genetic background.
[Show abstract][Hide abstract] ABSTRACT: PCR assays of naso- and oropharyngeal samples among hospitalized children appear equally effective for the diagnosis of serologically
confirmed community-acquired mycoplasmal pneumonia. However, the combination of results from both sites yields optimal sensitivity
(57%), specificity (98%), and positive (92%) and negative (82%) predictive values when compared with Mycoplasma pneumoniae enzyme-linked immunosorbent assay.
[Show abstract][Hide abstract] ABSTRACT: The precise epidemiology of childhood pneumonia remains poorly defined. Accurate and prompt etiologic diagnosis is limited by inadequate clinical, radiologic, and laboratory diagnostic methods. The objective of this study was to determine as precisely as possible the epidemiology and morbidity of community-acquired pneumonia in hospitalized children.
Consecutive immunocompetent children hospitalized with radiographically confirmed lower respiratory infections (LRIs) were evaluated prospectively from January 1999 through March 2000. Positive blood or pleural fluid cultures or pneumolysin-based polymerase chain reaction assays, viral direct fluorescent antibody tests, or viral, mycoplasmal, or chlamydial serologic tests were considered indicative of infection by those organisms. Methods for diagnosis of pneumococcal pneumonia among study subjects were published by us previously. Selected clinical characteristics, indices of inflammation (white blood cell and differential counts and procalcitonin values), and clinical outcome measures (time to defervescence and duration of oxygen supplementation and hospitalization) were compared among groups of children.
One hundred fifty-four hospitalized children with LRIs were enrolled. Median age was 33 months (range: 2 months to 17 years). A pathogen was identified in 79% of children. Typical respiratory bacteria were identified in 60% (of which 73% were Streptococcus pneumoniae), viruses in 45%, Mycoplasma pneumoniae in 14%, Chlamydia pneumoniae in 9%, and mixed bacterial/viral infections in 23%. Preschool-aged children had as many episodes of atypical bacterial LRIs as older children. Children with typical bacterial or mixed bacterial/viral infections had the greatest inflammation and disease severity. Multivariate logistic-regression analyses revealed that high temperature (> or = 38.4 degrees C) within 72 hours after admission (odds ratio: 2.2; 95% confidence interval: 1.4-3.5) and the presence of pleural effusion (odds ratio: 6.6; 95% confidence interval: 2.1-21.2) were significantly associated with bacterial pneumonia.
This study used an expanded diagnostic armamentarium to define the broad spectrum of pathogens that cause pneumonia in hospitalized children. The data confirm the importance of S pneumoniae and the frequent occurrence of bacterial and viral coinfections in children with pneumonia. These findings will facilitate age-appropriate antibiotic selection and future evaluation of the clinical effectiveness of the pneumococcal conjugate vaccine as well as other candidate vaccines.
[Show abstract][Hide abstract] ABSTRACT: To compare 2 days of antibiotic therapy (AT) to 4 days of AT in neonates with pneumonia and to assess the usefulness of neutrophil values (NV), C-reactive protein (CRP), and procalcitonin (PCT) in this population.
The study population consisted of consecutive, eligible term neonates begun on AT for suspected pneumonia. Of 51 neonates, 26 qualified for randomization (14, 2-day group; 12, 4-day group). NV were obtained with the initial evaluation and 12 and 24 hours later. CRP and PCT were obtained 12 and 48 hours after the initial evaluation.
None of the 12 neonates in the 4-day group developed recurrent respiratory symptoms. Three of the 14 neonates randomized to the 2-day group had recurrence of symptoms, resulting in study termination. NV, CRP, and PCT were similar in the 2- and 4-day groups. In the three neonates who developed respiratory symptoms, all absolute total neutrophil values and five out of nine absolute total immature neutrophil values were abnormal. However, all immature:total neutrophil values were normal, and CRP was strikingly elevated in only one neonate; only one of six PCT values was abnormal. In a secondary analysis of all 51 study neonates, CRP and PCT did not provide additional benefit over NV in differentiating neonates with pneumonia.
Four days of AT appears to be adequate for selected term neonates with pneumonia; however, 2 days of AT appears to be inadequate for this population. Relative to NV, CRP and PCT appear to have a limited role.
Journal of Perinatology 08/2003; 23(5):372-7. DOI:10.1038/sj.jp.7210949 · 2.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A prospective study of 154 consecutive high-risk hospitalized children with lower respiratory infections was conducted to determine the clinical utility of a pneumolysin-based polymerase chain reaction (PCR) assay compared with blood and pleural fluid cultures and serological and urinary antigen tests to determine the incidence of Streptococcus pneumoniae. Whole blood, buffy coat, or plasma samples from 67 children (44%) tested positive by PCR. Sensitivity was 100% among 11 promptly tested culture-confirmed children and specificity was 95% among control subjects. Age, prior oral antibiotic therapy, and pneumococcal nasopharyngeal colonization did not influence PCR results, whereas several surrogates of disease severity were associated with positive tests. Although serological and urinary antigen tests had comparable sensitivity, specificity varied among infected children, and statistical agreement among all assays was limited. These findings support the use of PCR tests to evaluate the protective efficacy of pneumococcal conjugate vaccines and to identify promptly children with pretreated or nonbacteremic pneumococcal lower respiratory infections.
[Show abstract][Hide abstract] ABSTRACT: Because chronic Mycoplasma pneumoniae respiratory infection is hypothesized to play a role in asthma, the potential of M. pneumoniae to establish chronic respiratory infection with associated pulmonary disease was investigated in a murine model. BALB/c mice
were intranasally inoculated once with M. pneumoniae and examined at 109, 150, 245, 368, and 530 days postinoculation. M. pneumoniae was detected in bronchoalveolar lavage fluid by culture or PCR in 70 and 22% of mice at 109 and 530 days postinoculation,
respectively. Lung histopathology was normal up to 368 days postinoculation. At 530 days, however, 78% of the mice inoculated
with M. pneumoniae demonstrated abnormal histopathology characterized by peribronchial and perivascular mononuclear infiltrates. A mean histopathologic
score (HPS) at 530 days of 5.1 was significantly greater (P < 0.01) than that for controls (HPS score of 0). Serum anti-M. pneumoniae immunoglobulin G was detectable in all of the mice inoculated with M. pneumoniae and was inversely correlated with HPS (r = −0.95, P = 0.01) at 530 days postinoculation. Unrestrained whole-body plethysmography measurement of enhanced pause revealed significantly
elevated airway methacholine reactivity in M. pneumoniae-inoculated mice compared with that in controls at 245 days (P = 0.03) and increased airway obstruction at 530 days (P = 0.01). Murine M. pneumoniae respiratory infection can lead to chronic pulmonary disease characterized by airway hyperreactivity, airway obstruction,
and histologic inflammation.
Infection and Immunity 02/2002; 70(2):649-54. DOI:10.1128/IAI.70.2.649-654.2002 · 3.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BMS-284756 is a novel des-fluoro(6) quinolone with a broad antimicrobial activity, including Streptococcus pneumoniae. The purpose of this study was to evaluate the pharmacodynamic profile and effectiveness of BMS-284756 for therapy of experimental meningitis caused by penicillin- and cephalosporin-resistant S. pneumoniae (CRSP). Meningitis was induced in rabbits by intracisternal inoculation of CRSP. BMS-284756 was given intravenously 16 h after intracisternal inoculation in single doses of 2.5 (n = 5 animals), 5 (n = 6), 10 (n = 6), 20 (n = 8), and 30 mg/kg (n = 6), in two doses of 10 mg/kg each separated by 5 h (n = 4), and as a 20-mg/kg dose followed 5 h later by 10 mg/kg (n = 5). The MICs and MBCs of BMS-284756, ceftriaxone, and vancomycin were 0.06 and 0.06, 4 and 4, and 0.25 and 0.25 microg/ml, respectively. After single doses of 10, 20, and 30 mg/kg, the maximum concentrations in cerebrospinal fluid (CSF) (mean +/- standard deviation) were 0.32 +/- 0.12, 0.81 +/- 0.38, and 1.08 +/- 0.43 microg/ml, respectively; the elimination half-life in CSF was 4.5 to 6.3 h. The CSF bacterial killing rates (BKR) at 5 h of the single-dose regimens of 10, 20 and 30 mg/kg were -0.84 +/- 0.48, -1.09 +/- 0.32, and -1.35 +/- 0.05 Deltalog(10) CFU/ml/h. The BKR(0-5) of the divided regimens (10 mg/kg twice and 20 mg/kg followed by 10 mg/kg) was -0.82 +/- 0.52 and -1.24 +/- 0.34 Deltalog(10) CFU/ml/h, respectively. The BKR(0-5) of the combined therapy with vancomycin and ceftriaxone was -1.09 +/- 0.39 Deltalog(10) CFU/ml/h. The penetration of BMS-284756 into purulent CSF relative to plasma was 14 to 25%. The bactericidal effect of BMS-284756 in CSF was concentration dependent. BMS-284756 at 30 mg/kg as a single or divided dose was as effective as standard therapy with vancomycin and ceftriaxone.
[Show abstract][Hide abstract] ABSTRACT: Moxifloxacin, an 8-methoxyquinolone with broad-spectrum activity in vitro, was studied in the rabbit model of Escherichia coli meningitis. The purposes of this study were to evaluate the bactericidal effectiveness and the pharmacodynamic profile of moxifloxacin in cerebrospinal fluid (CSF) and to compare the bactericidal activity with that of ceftriaxone and meropenem therapy. After induction of meningitis, animals were given single doses of 10, 20, and 40 mg/kg or divided-dose regimens of 5, 10, and 20 mg/kg twice, separated by 6 h. After single doses, the penetration of moxifloxacin into purulent CSF, measured as percentage of the area under the concentration-time curve (AUC) in CSF relative to the AUC in plasma, was approximately 50%. After single doses of 10, 20, and 40 mg/kg, the maximum CSF concentration (C(max)) values were 1.8, 4.2, and 4.9 microg/ml, respectively; the AUC values (total drug) were 13.4, 25.4, and 27.1 microg/ml x h, respectively, and the half-life values (t(1/2)) were 6.7, 6.6, and 4.7 h, respectively. The bacterial killing in CSF for moxifloxacin, calculated as the Deltalog(10) CFU per milliliter per hour, at 3, 6, and 12 h after single doses of 10, 20, and 40 mg/kg were -5.70, -6.62, and -7.02; -7.37, -7.37, and -6.87; and -6.62, -6.62, and -6.62, respectively, whereas those of ceftriaxone and meropenem were -4.18, -5.24, and -4.43, and -3.64, -3.59, and -4.12, respectively. The CSF pharmacodynamic indices of AUC/MBC and C(max)/MBC were interrelated (r = 0.81); there was less correlation with T > MBC (r = 0.74). In this model, therapy with moxifloxacin appears to be at least as effective as ceftriaxone and more effective than meropenem therapy in eradicating E. coli from CSF.
[Show abstract][Hide abstract] ABSTRACT: Because Mycoplasma pneumoniae is hypothesized to play an important role in reactive airway disease/asthma, a comprehensive murine model of M. pneumoniae lower respiratory infection was established. BALB/c mice were intranasally inoculated once withM. pneumoniae and sacrificed at 0 to 42 days postinoculation. All mice became infected and developed histologic evidence of acute pulmonary
inflammation, which cleared by 28 days postinoculation. By contrast, M. pneumoniae persisted in the respiratory tract for the entire 42 days studied. Tumor necrosis factor alpha, gamma interferon, interleukin-6
(IL-6), KC (functional IL-8), MIP-1α, and MCP-1/JE concentrations were significantly elevated in bronchoalveolar lavage samples,
whereas IL-4 and IL-10 concentrations were not significantly elevated. Pulmonary airflow resistance, as measured by plethysmography,
was detected 1 day postinoculation and persisted even after pulmonary inflammation had resolved at day 28. Serum anti-M. pneumoniae immunoglobulin G titers were positive in all mice by 35 days. This mouse model provides a means to investigate the immunopathogenesis
of M. pneumoniae infection and its possible role in reactive airway disease/asthma.
Infection and Immunity 07/2001; 69(6):3869-76. DOI:10.1128/IAI.69.6.3869-3876.2001 · 3.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: An immunocompetent murine model of pneumococcal pneumonia and bacteremia was used to evaluate a PCR assay based on amplification of the pneumolysin gene. Mice were treated with trovafloxacin to determine the decline in sensitivity of PCR as lung bacterial concentrations decreased and blood cultures became sterile. Forty-three mice were studied for up to 120 h after start of antibiotic treatment. PCR of buffy coat specimens was more sensitive than PCR of plasma. Only 21% of animals had a positive blood culture, whereas 77% of PCR buffy coat assays were positive. After 48 h of therapy all blood culture specimens were sterile, whereas buffy coat PCR was positive in 57.8% of specimens. PCR of buffy coat specimens was negative in all mice colonized nasally with Streptococcus pneumoniae and in rabbits with Escherichia coli bacteremia. Our results demonstrate that our PCR technique using buffy coat specimens is highly specific for invasive pneumococcal disease and remains positive in the majority of animals for at least 48 h after start of antibiotic therapy.
[Show abstract][Hide abstract] ABSTRACT: The broad antimicrobial spectrum and affordable price of chloramphenicol make it an attractive first line treatment option for children with severe illnesses in developing countries. Little is known, however, about its pharmacokinetics in young infants in these settings.
We studied infants younger than 3 months of age hospitalized in Manila, Philippines and The Gambia with possible severe bacterial infections likely to benefit from treatment with chloramphenicol. Infants in the first week of life received intramuscular doses of 25 mg/kg chloramphenicol once daily, twice daily in the second through fourth week of life and three times daily from 5 to 12 weeks of age. Blood samples were taken at 0.5, 1, 2 and 3 h after the first dose, 1 h before the second dose and before the repetition doses on subsequent days. In the Philippines a second group of infants was treated with oral chloramphenicol according to the same dosage schedule.
Thirty-eight infants received intramuscular chloramphenicol, and 20 received oral drug. Intramuscular administration resulted in therapeutic concentrations (10 to 25 microg/ml) in 73 to 86% of children in each of the three age groups in the first 6 h and in 50 to 80% on Days 2 and 3. Between 33 and 38% of children had potentially toxic values on Days 2 and 3. In contrast, after oral administration, only about one-half of the children reached therapeutic values in serum at any time up to Day 3 after start of treatment.
Intramuscular chloramphenicol can be used as a second line drug for the treatment of severe infections in infants younger than 90 days of age, where third generation cephalosporins are not available. It quickly achieves therapeutic values in a high proportion of children. However, severe infections should not be treated with oral chloramphenicol in this age group, because therapeutic serum concentrations were inconsistently achieved.
[Show abstract][Hide abstract] ABSTRACT: Trovafloxacin is a recently approved fluoroquinolone with excellent activity against gram-positive and gram-negative organisms that offers a potential alternative for treatment of beta-lactam-resistant pneumococcal meningitis. Using the rabbit meningitis model, we sought to characterize the pharmacodynamic properties of trovafloxacin in the cerebrospinal fluid (CSF). Animals were given single doses of trovafloxacin of 10, 15, 20 or 30 mg/kg; 1 h after Infusion mean CSF concentrations were 0.59+/-0.18, 0.74+/-0.14, 1.12+/-0.12 and 1.07+/-0.35 mg/L, respectively. The bacterial killing rate Increased with increasing dosages of trovafloxacin, indicating that its activity is concentration dependent. All three pharmacodynamic Indices (area under the concentration curve (AUC)/MBC, peak concentration (Cmax)/MBC, and time above MBC (T > MBC)) correlated with bacterial killing; however, AUC/MBC correlated best (r = 0.71). In a second experiment we found comparable bacterial killing with multiple doses of trovafloxacin given either every serum half-life or every two serum half-lives. In both experiments bacterial regrowth occurred when the concentration of trovafloxacin in CSF fell below the MBC. These data have been used in formulating an appropriate regimen for trovafloxacin treatment of bacterial meningitis in children.
[Show abstract][Hide abstract] ABSTRACT: To investigate the pathogenesis of acute Mycoplasma pneumoniae infection, BALB/c mice were anesthetized with metofane, and M. pneumoniae was introduced intranasally on days 0, 1, and 2. Mice were sacrificed on days 0-15. A histopathologic scoring system defined inflammatory changes in the lungs on a scale of 0-26 (least to most severe). Broth cultures were positive for all nasal passage and bronchoalveolar lavage (BAL) specimens. Histopathologic scores ranged from 0 to 21. The mean log10 (cfu/mL) were 4.1-6.4 on days 1-10 and >/=1.7 on days 13-15 for nasal passage and BAL specimens. Serum polymerase chain reaction was negative. ELISA for serum IgM and immunoblots for M. pneumoniae antibody were positive in 21 (62%) of 34 and 33 (97%) of 34 infected animals, respectively, at days 8-15. ELISA for IgG antibody was negative. This mouse pneumonia model can be used to study the immunologic and therapeutic responses to acute M. pneumoniae infection.
The Journal of Infectious Diseases 11/1998; 178(5):1526-9. DOI:10.1086/314439 · 6.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine the importance of Mycoplasma pneumoniae and Chlamydia pneumoniae in community-acquired pneumonia (CAP) of children from different latitudes and to compare clinical outcome using azithromycin (AZM) versus either amoxicillin-clavulanate (A-C) or erythromycin estolate (EE).
Ambulatory patients with CAP were identified at either the Children's Medical Center of Dallas, Texas or the Hospital del Niño of Panama City, Panama. Children 6 months to 15 years of age were enrolled and randomized to receive either AZM for 5 days or a 10 day course of either A-C or EE, for those younger or older than 5 years of age, respectively. Mycoplasma pneumoniae and C. pneumoniae were identified by measuring acute and convalescent serum antibody titers and by performing nasopharyngeal (NP) and oropharyngeal (OP) swabs for culture and polymerase chain reaction (PCR) testing.
Overall 335 patients (168 in Dallas and 167 in Panama) were evaluated from February 1996 through December 1997. Acute M. pneumoniae infection was detected in 12 (7%) patients each in Dallas and Panama. Acute C. pneumoniae infection was observed in 10 (6%) children at each site. Infection caused by these "atypical" microorganisms occurred more frequently in children older than 5 years of age (23% vs 9%, P = 0.001, RR 2.5, 95% CI 1.4-4.3). No distinctive pattern of clinical or radiologic abnormalities was seen in relation to etiology. Clinical cure was achieved in 43 of 44 children infected by these bacteria regardless of treatment assignment.
Mycoplasma pneumoniae and C. pneumoniae are common etiologic agents of CAP in older children from different latitudes. Children with CAP present with similar clinical and radiologic findings to those caused by other etiologic agents. Outcome was excellent for the three treatment regimens studied.
[Show abstract][Hide abstract] ABSTRACT: Interleukin-10 (IL-10) is a cytokine with antiinflammatory effects. In a rabbit model of meningitis, IL-10 was given intracisternally or intravenously to evaluate the impact on inflammation induced by lipooligosaccharide (LOS), Haemophilus influenzae type b (Hib), or Listeria monocytogenes. Intracisternal IL-10 in concentrations >1 microg significantly reduced tumor necrosis factor-alpha (TNF-alpha) and lactate values in cerebrospinal fluid (CSF). Intravenous IL-10 (1 mg/kg) in two doses after intracisternal LOS significantly reduced CSF TNF-alpha and lactate. When Hib was used, animals were treated with ceftriaxone and dexamethasone with or without IL-10 (1 mg/kg). TNF-alpha was significantly reduced in animals treated with IL-10, dexamethasone, or both compared with levels in rabbits receiving ceftriaxone alone. Comparable results were obtained when L. monocytogenes was inoculated and animals were treated with ampicillin with or without IL-10, dexamethasone, or nothing. In conclusion, IL-10 modulates CSF TNF-alpha concentrations in experimental LOS, Hib, or L. monocytogenes meningitis. The maximal inhibitory effect was seen when IL-10 and dexamethasone were combined.
The Journal of Infectious Diseases 11/1997; 176(5):1239-46. DOI:10.1086/514118 · 6.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Adequate concentrations of beta-lactam antibiotics in cerebrospinal fluid (CSF) are difficult to achieve for meningitis caused by drug-resistant Streptococcus pneumoniae. Ceftriaxone in dosages of 150 or 400 mg/kg of body weight per day, given in one or two doses, was used for the treatment of experimental highly cephalosporin-resistant (MIC and MBC, 4 microg/ml) pneumococcal meningitis. The bacterial killing rate (delta log10 CFU per milliliter per hour) and pharmacokinetic indices, including percentage of time the antibiotic concentration exceeded the MBC during a 24-h period (T>MBC), CSF peak concentration above the MBC, and area under the concentration-time curve from 0 to 24 h above MBC, were measured and correlated. By multiple stepwise regression, only T>MBC independently predicted the bacterial killing rate. There was a direct linear correlation between T>MBC in CSF and the bacterial killing rate during the first 24 h of therapy (r = 0.87; P = 0.004). Sterilization of CSF was achieved only when the T>MBC was 95 to 100%. In the first 24 h, the 200-mg/kg/12-h regimen, compared with the 400-mg/kg/24-h regimen, was associated with a greater T>MBC (87% +/- 10% versus 60% +/- 22%; P = 0.03) and greater bacterial killing rate (0.2 +/- 0.04 versus 0.13 +/- 0.07; P = 0.003), confirming that ceftriaxone exhibits time-dependent bactericidal activity. After 24 h, the T>MBC and the CSF sterilization rates were similar whether ceftriaxone was given once or twice daily.
Antimicrobial Agents and Chemotherapy 11/1997; 41(11):2414-7. · 4.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine the utility of polymerase chain reaction (PCR) assay of cerebrospinal fluid (CSF), serum, and urine for rapid diagnosis of enteroviral meningitis in infants 3 months of age and younger.
We identified prospectively infants 3 months of age and younger coming to the emergency department with fever whose examination included a lumbar puncture, blood culture, or both. Samples of CSF, serum, urine, throat, and stool specimens were collected for viral culture and, with the exception of stool, for PCR assay. Those infants who had not received prior antibiotic therapy and had sterile bacterial cultures of CSF, blood, and urine were selected for the present analysis.
A total of 259 specimens for viral culture and 203 specimens for PCR assay were collected from 64 infants. Comparison of results of PCR assay of CSF with viral culture, the gold standard for diagnosis of enteroviral meningitis, demonstrated a sensitivity of 100% and a specificity of 90%. Because enteroviruses are not always detectable by culture, the following modified standard was established to define enteroviral meningitis: either CSF pleocytosis, sterile bacterial cultures and detection of an enterovirus in stool culture or positive viral culture of CSF, or both. With this modified definition, the sensitivity and specificity of the PCR assay of CSF were 92% and 94%, respectively. PCR assay of serum and urine offered no benefit over PCR assay of CSF alone for diagnosis of meningitis.
PCR assay of CSF is useful for the rapid and reliable diagnosis of enteroviral meningitis. Application of this technique in the clinical setting can potentially diminish unnecessary hospitalization and use of antibiotics.
Journal of Pediatrics 10/1997; 131(3):393-7. DOI:10.1016/S0022-3476(97)80064-9 · 3.79 Impact Factor