Faryal Ghaffar

Effect of the 7-Valent Pneumococcal Conjugate Vaccine on Nasopharyngeal Colonization by Streptococcus pneumoniae in the First 2 Years of Life

BACKGROUND Studies suggest that the 7-valent pneumococcal conjugate vaccine (PCV7) reduces carriage of vaccine-type (VT) Streptococcus pneumoniae (SP). We studied the effect of PCV7 on carriage of VT- and non-VT (NVT) SP, by studying the effect of PCV7 on nasopharyngeal (NP) colonization by VT and NVT SP during early childhood. METHODS At 2 months of age, 278 infants were enrolled in this study. To determine carriage of SP, NP samples were obtained before each PCV7 dose, at 9 months of age, and 2-3 months after the booster dose of vaccine. RESULTS The carriage of SP increased slightly, from 12% (95% confidence interval [CI], 8%-16%) of subjects at 2 months of age to 18% (95% CI, 13%-23%) at 4 months of age (P<.05). Carriage of SP remained in 24%-30% of subjects during subsequent months. Between the 12- and 18-month visits, the carriage rate of VT SP decreased significantly, from 18% (95% CI, 13%-23%) to 9% (95% CI, 5%-13%) of subjects (P=.001). The trend of a decrease in carriage of penicillin-nonsusceptible SP, from 16% of subjects (95% CI, 11%-21%) at the 12-15-month visit to 9% (95% CI, 5%-13%) at the 15-18-month visit, was found after the booster dose of vaccine. CONCLUSION The reduction of VT-SP colonization and replacement by NVT SP after the booster dose of vaccine suggests the possibility that widespread vaccination will result in replacement of pneumococci mainly by antibiotic-susceptible NVT SP.

Impact of the Pneumococcal Conjugate Vaccine on Serotype Distribution and Antimicrobial Resistance of Invasive streptococcus pneumoniae Isolates in Dallas, Tx, Children From 1999 Through 2005

Background: Because the heptavalent pneumococcal conjugate vaccine has reduced vaccine-type invasive pneumococcal disease (IPD) in children, a greater proportion of IPD is now caused by nonvaccine (NVT) serotypes. We analyzed the serotypes, antimicrobial resistance profiles and genetic relatedness of Streptococcus pneumoniae responsible for IPD at Childrens Medical Center of Dallas. Methods: S. pneumoniae isolates were collected from January 1, 1999 through December 31, 2005. Incidence of IPD was calculated using inpatient and emergency center admissions to Childrens Medical Center of Dallas as the denominator. Isolates were serotyped, and their penicillin and cefotaxime susceptibility determined. The 19A isolates were further characterized by pulsed-field gel electrophoresis, multilocus sequence typing and determination of penicillin-binding proteins and mef and erm genes. Results: The incidence of IPD decreased from 93.6 cases/100,000 patients in 1999 to a nadir of 41 cases/100,000 patients in 2003 (P < 0.001). The number of IPD cases caused by serotype 19A increased, accounting for 40% of the cases of IPD in 2005. Penicillin and cefotaxime susceptibility of IPD isolates did not change from 1999 through 2005 (P = 0.687). There was a decrease in penicillin (P < 0.001) and cefotaxime (P = 0.034) susceptibility in NVT serotypes from 1999 to 2005. Molecular characterization of 19A isolates revealed a predominance of ST-199 (62%). Several highly penicillin-resistant and intermediately cefotaxime-resistant strains emerged in 2004 and 2005. Conclusions: In Dallas, heptavalent pneumococcal conjugate vaccine reduced the incidence of IPD from 1999 to 2005 by reducing the incidence of vaccine-type disease. NVT serotypes, particularly 19A, were prevalent and more resistant to antimicrobials in 2004 and 2005.

Mobilization of Plasmacytoid and Myeloid Dendritic Cells to Mucosal Sites in Children with Respiratory Syncytial Virus and Other Viral Respiratory Infections

BACKGROUND Respiratory syncytial virus (RSV) is the principal etiologic agent of bronchiolitis and viral pneumonia in infants and young children. Yet, many aspects of its immunopathogenesis are not well understood. METHODS We analyzed the immune cells that are mobilized by RSV and other respiratory viruses, by studying nasal wash samples from children hospitalized with acute viral respiratory infections. RESULTS RSV mobilizes virtually all blood immune cells, including myeloid dendritic cells (DCs) and plasmacytoid DCs (pDCs), to the nasal mucosa. DCs were also mobilized to the nasal mucosa of children with other viral respiratory infections. The increased number of pDCs in the nasal compartment significantly correlates with RSV load (P=.022), and it is associated with a significant decrease in the number of pDCs in the blood (P=.007). The influx of DCs in the nasal mucosa is not transient, as even higher numbers of both DC subsets were found in respiratory secretions weeks after the acute symptoms of RSV infection had resolved. Immunochemistry analysis of respiratory samples has demonstrated the presence of the RSV fusion protein within HLA-DR-positive cells. CONCLUSION Infection with RSV and other respiratory viruses mobilizes DCs to the site of viral entry.

Diagnosis of Streptococcus pneumoniae Lower Respiratory Infection in Hospitalized Children by Culture, Polymerase Chain Reaction, Serological Testing, and Urinary Antigen Detection

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.

Acute mastoiditis in children : a seventeen-year experience in Dallas, Texas

Background. In the preantibiotic era acute mastoiditis was the most common complication of acute otitis media, often resulting in substantial morbidity and mortality. Since 1989 several investigators have documented an increased frequency of acute mastoiditis in children. Methods. The medical records of all children with a discharge diagnosis of acute mastoiditis, managed at Children’s Medical Center, Dallas, TX, from 1983 through 1999 were reviewed. Results. There were 57 cases of acute mastoiditis during the 17-year period of 1983 through 1999 compared with 57 cases in a 25-year period of 1955 through 1979 reported previously at the same institution. The number of cases of acute mastoiditis per 10 000 hospital admissions increased significantly (regression analysis P = 0.003) during the more recent 17 years. From 1993 through 1999 there were 4.5 cases or more per 10 000 admissions each year, whereas from 1983 through 1992, the incidence never exceeded 4.3 cases per 10 000 admissions (P = 0.018). The median age of the patients was 48 months. Twenty-two patients (38.5%) were younger than 24 months; 17 of these were 12 months of age or younger. Twenty-two (38.5%) patients had no history of previous episodes of acute otitis media. Streptococcus pneumoniae was the pathogen most often isolated from the cultures. Complications of mastoiditis occurred in 20 children (35%). Conclusions. We conclude that acute mastoiditis continues to be a problem in the post antibiotic era. It occurs mainly in young children and can be the first evidence of ear disease.

Effects of Large Dosages of Amoxicillin/Clavulanate or Azithromycin on Nasopharyngeal Carriage of Streptococcus pneumoniae, Haemophilus influenzae, Nonpneumococcal α-Hemolytic Streptococci, and Staphylococcus aureus in Children with Acute Otitis Media

Prior use of antibiotics is associated with carriage of resistant bacteria. Colonization by Streptococcus pneumoniae, Haemophilus influenzae, nonpneumococcal alpha-hemolytic streptococci (NPAHS), and Staphylococcus aureus was evaluated in children receiving antibiotic therapy for acute otitis media and in untreated, healthy control subjects. Children were randomly assigned to receive either amoxicillin/clavulanate (90 mg/kg per day) or azithromycin. Swabs were obtained before initiating therapy and again 2 weeks and 2 months after initiating therapy. We also obtained swabs from control subjects at the time of enrollment and 2 weeks and 2 months after enrollment. The decrease in the rate of carriage of S. pneumoniae and H. influenzae at 2 weeks was significant only in the amoxicillin/clavulanate group (P<.001 and P=.005, respectively). The rate of nasopharyngeal colonization with NPAHS among treated patients increased from 23% to 39% at 2 months (P=.01). This increase was similar for both treatment groups. These results suggest that the competitive balance between organisms is altered by antibiotic therapy.

Effects of Amoxicillin/Clavulanate or Azithromycin on Nasopharyngeal Carriage of Streptococcus pneumoniae and Haemophilus influenzae in Children with Acute Otitis Media

The effect of antibiotic therapy on nasopharyngeal colonization by Streptococcus pneumoniae and Haemophilus influenzae was evaluated in children diagnosed with acute otitis media. Children were randomly assigned to receive either amoxicillin/clavulanate or azithromycin therapy, and nasopharyngeal swabs were obtained for culture before and after starting therapy. Amoxicillin/clavulanate therapy eradicated or suppressed all strains of S. pneumoniae susceptible to penicillin, 75% of strains with intermediate resistance, and 40% of strains resistant to penicillin. Azithromycin therapy cleared two-thirds of azithromycin-susceptible strains of S. pneumoniae but none of azithromycin-nonsusceptible strains. Selection for antibiotic-resistant strains in individual children was not observed in children who received amoxicillin/clavulanate therapy but was observed in 2 children who received azithromycin therapy. Carriage of H. influenzae was also reduced by antimicrobial therapy but more so by amoxicillin/clavulanate. Antibiotic therapy does not directly increase the number of resistant strains in the population but, by eradicating susceptible strains, allows greater opportunity for carriage and spread of resistant strains.

Pharmacodynamics and Bactericidal Activity of Moxifloxacin in Experimental Escherichia coli Meningitis

ABSTRACT Moxifloxacin, an 8-methoxyquinolone with broad-spectrum activity in vitro, was studied in the rabbit model of Escherichia colimeningitis. 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 (Cmax) values were 1.8, 4.2, and 4.9 μg/ml, respectively; the AUC values (total drug) were 13.4, 25.4, and 27.1 μg/ml · h, respectively, and the half-life values (t½) were 6.7, 6.6, and 4.7 h, respectively. The bacterial killing in CSF for moxifloxacin, calculated as the Δlog10 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 Cmax/MBC were interrelated (r = 0.81); there was less correlation withT > 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 eradicatingE. coli from CSF.

Increased carriage of resistant non-pneumococcal α-hemolytic streptococci after antibiotic therapy

OBJECTIVE We compared colonization and resistance rates of non-pneumococcal alpha-hemolytic streptococci (AHS) and Streptococcus pneumoniae in children receiving antibiotic therapy for acute otitis media. STUDY DESIGN Between December 1997 and September 1998, children 6 months to 6 years of age, diagnosed with acute otitis media were randomly assigned to receive amoxicillin/clavulanate (Augmentin) 45 mg/kg/d in 2 divided doses for 10 days or azithromycin (Zithromax), 10 mg/kg, once on the first day, followed by 5 mg/kg daily for 4 days. Nasopharyngeal swabs for culture were obtained before and at 2 weeks and 2 months after the start of therapy. Streptococci were identified by species, and antibiotic susceptibility was determined by the epsilometric test. RESULTS One hundred six children completed the 2-week follow-up and 2-month follow-up, respectively. The nasopharyngeal carriage rate of non-pneumococcal AHS increased from 14% before treatment to 32% at the 2-week follow-up (P =.02) and was similar in both treatment groups. In contrast, the carriage of S pneumoniae decreased from 51% before therapy to 27% at the 2-week follow-up (P =.002). The carriage of penicillin-resistant AHS strains (minimum inhibitory concentration > 1 microg/mL) increased from 9% before treatment to 26% at 2 weeks and 36% at 2 months. CONCLUSIONS Amoxicillin/clavulanate and azithromycin therapy resulted in increased isolation of nasopharyngeal non-pneumococcal AHS, many of which were multidrug-resistant, in contrast to a decrease in pneumococcal carriage. This suggests that the competitive balance between these 2 groups of organisms was disturbed as a result of differential antibiotic susceptibility. The importance of drug-resistant AHS as a reservoir for resistance genes for S pneumoniae warrants further investigation.

BMS-284756 in Experimental Cephalosporin-Resistant Pneumococcal Meningitis

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 μg/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 μg/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 Δlog10 CFU/ml/h. The BKR0–5 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 Δlog10CFU/ml/h, respectively. The BKR0–5 of the combined therapy with vancomycin and ceftriaxone was −1.09 ± 0.39 Δlog10 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.