Optochin resistance in Streptococcus pneumoniae: mechanism, significance, and clinical implications.

Traditionally, Streptococcus pneumoniae is identified in the laboratory by demonstrating susceptibility to optochin. Between 1992 and 1998, 4 pneumococcal isolates exhibiting optochin resistance were recovered from patients at Children's National Medical Center. Three of the 4 isolates consisted of mixed populations of optochin-resistant and -susceptible organisms. Both subpopulations had identical antibiograms, serotypes, and restriction fragment profiles. The other isolate was uniformly resistant to optochin. Resistant strains had MICs of optochin 4-30-fold higher than susceptible strains, belonged to different serotypes, and had dissimilar restriction fragment profiles, indicating clonal unrelatedness. Resistance arose from single point mutations in either the a-subunit (W206S) or the c-subunit (G20S, M23I, and A49T) of H(+)-ATPase. There is speculation of a possible association between exposure to antimalarial drugs and evolution of optochin resistance. alpha-Hemolytic streptococci resistant to optochin, particularly invasive isolates, should be tested for bile solubility or with an S. pneumoniae DNA probe before identification as viridans streptococci.

Soft tissue and cartilage infection by Salmonella oranienburg in a healthy girl.

Focal extraintestinal infections from nontyphoid salmonellae have increased in incidence during the past decade. Typically, they are manifested as either osteomyelitis or meningitis as a complication of either bacteremia or enteric fever. Isolated salmonellal soft tissue infections, however, are rare and occur mostly in adults with chronic underlying conditions such as human immunodeficiency virus (HIV) infection, diabetes mellitus, and cell-mediated immunity defects. We report a case of an otherwise healthy adolescent who was exposed to a guinea pig with a skin mass. She subsequently had an isolated soft tissue infection with cartilaginous involvement of the anterior chest wall due to Salmonella enterica serogroup C1 (bioserotype oranienburg).

Prospective, randomized, investigator-blinded study of the efficacy and safety of meropenem vs. cefotaxime therapy in bacterial meningitis in children. Meropenem Meningitis Study Group.

OBJECTIVES: To compare the efficacy and safety of meropenem with cefotaxime for the treatment of infants and children with bacterial meningitis. METHODS: Infants and children with strongly suspected or documented bacterial meningitis were randomly assigned in a prospective multicenter study to receive either meropenem or cefotaxime. Patients were assessed at the end of therapy and at 5 to 7 weeks and 5 to 7 months after the end of treatment for the presence of neurologic and sensory neural sequelae. RESULTS: A total of 258 children were randomized to either treatment group. A further 8 patients with suspected pneumococcal meningitis were treated with meropenem without randomization. Of the randomized patients 154 were fully evaluable, 79 in the meropenem group and 75 in the cefotaxime group. At the end of treatment there were no significant differences in clinical outcome between the two treatment groups. Clinical cure with or without sequelae was achieved in 97 and 96% of the meropenem- and cefotaxime-treated patients, respectively. At the end of treatment and at 5 to 7 weeks, 46 and 54% of meropenem patients were cured with no sequelae, respectively. Corresponding results for cefotaxime patients were 56 and 58%. All pathogens were eradicated. In total 37 patients had seizures during treatment, 15 (12%) in the meropenem and 22 (17%) in the cefotaxime group. None of the seizures was considered to be drug-related. CONCLUSIONS: This trial shows that meropenem is suitable therapy for bacterial meningitis in infants and children and that it offers an efficacy and safety profile similar to that of cefotaxime.

Management strategies for respiratory syncytial virus infections in infants.

Management of respiratory syncytial virus lower respiratory tract infection in infants is predominantly supportive and symptomatic. Outpatient management requires close attention to feeding, oral hydration, and monitoring of fever, behavior, and respiratory effort. In the small proportion of patients who need hospitalization, clinicians are concerned primarily with oxygenation and the possibility of oxygen desaturation. Appropriate interventions depend on the level of oxygenation as indicated by pulse oximetry or arterial blood gases. Hydration and symptomatic treatment with alpha- or ss(2 )-adrenergic agonist bronchodilators may lessen the work of breathing. The role of these agents remains controversial, however, and anticholinergic bronchodilators are considered ineffective. Current antiviral therapy is limited to aerosolized ribavirin. Immunotherapy with respiratory syncytial virus immune globulin or a monoclonal antibody has not been rewarding in terms of clinical outcome, although the antiviral effect of these agents has been impressive. There is concern about long-term pulmonary sequelae after respiratory syncytial virus lower respiratory tract infection early in life. Several recent studies, including new data reported here, suggest that ribavirin may have a beneficial effect on some of these sequelae, whereas other studies have failed to demonstrate any benefit. Future studies may help resolve this question.

Safety and pharmacokinetics of an intramuscular monoclonal antibody (SB 209763) against respiratory syncytial virus (RSV) in infants and young children at risk for severe RSV disease.

We conducted a multicenter, double-blind, placebo-controlled, randomized trial of a humanized monoclonal antibody against a respiratory syncytial virus (RSV) fusion protein (SB 209763) to evaluate its safety, pharmacokinetics, and fusion inhibition and neutralization titers. Forty-three infants who were either delivered prematurely (

Prospective follow-up and pulmonary functions from a placebo-controlled randomized trial of ribavirin therapy in respiratory syncytial virus bronchiolitis. Ribavirin Study Group.

OBJECTIVE: To determine any long-term differences in adverse effects and pulmonary function between infants with respiratory syncytial virus and lower respiratory tract infection who were treated with ribavirin and a control group. STUDY DESIGN: Long-term follow-up included enumeration of episodes of respiratory illness, wheezing, and pneumonia and, ultimately, administration of pulmonary function tests (PFTs). Pulse oximetry was done at each visit. During the first 3 years we conducted follow-up in the fall and spring. In years 4 and 5 we conducted 1 visit per year. During years 5 through 7 we conducted PFTs, and starting with year 7 a methacholine chloride challenge was done if forced expiratory volume in 1 second (FEV1) was greater than 70% of predicted value. RESULTS: We prospectively enrolled (December 1983 to February 1985) in a randomized trial of ribavirin vs placebo children who were previously healthy, were premature, or had chronic pulmonary disease. One pulmonologist (R.F.; blinded) scored and interpreted the results of the PFTs. We studied 42 patients aged 1 to 33 months; 2 patients died (1 receiving ribavirin and 1 receiving placebo) and 5 patients receiving placebo were lost to follow-up; 35 patients (24 taking ribavirin and 11 taking placebo) attended 212 visits. Four patients were premature (3 in the ribavirin and 1 in the placebo group), and 3 of these had bronchopulmonary dysplasia (2 in the ribavirin and 1 in the placebo group). From years 1 to 3, there was more reactive airway disease, wheezing, and pneumonia in the placebo than in the ribavirin group (mean score, 22.3 for 12 placebo-treated patients vs. 15.8 for 23 ribavirin-treated patients; P = .07 by Kruskal-Wallis test); for all years, it was 22.0 for 11 placebo-treated patients vs. 16.0 for 22 ribavirin-treated patients (P = .10). After informed consent was given, 19 patients completed PFTs (13 receiving ribavirin and 6 receiving placebo); 7 of 13 ribavirin-treated patients (53%) had normal or mild PFT results vs. 0 of 6 placebo-treated patients (P = .04 by Fisher exact test). On methacholine challenge (7 ribavirin-treated patients and 5 placebo-treated patients), there was more reactivity in the placebo vs. the ribavirin group (exact P = .07). Scoring done by weighting for severity for 19 patients (13 ribavirin-treated patients and 6 placebo-treated patients) (even after correcting for asthma) showed a significant difference in favor of previously ribavirin-treated patients (exact P = .02). CONCLUSIONS: No outward effects were identified from ribavirin exposure. We observed no increase in reactive airway disease, wheezing, and pneumonia in the ribavirin compared with the placebo group. Weighted severity scores suggest long-term beneficial effect of ribavirin therapy; however, larger numbers should be evaluated.

A conservative amino acid mutation in the chromosome-encoded dihydrofolate reductase confers trimethoprim resistance in Streptococcus pneumoniae.

Multidrug-resistant Streptococcus pneumoniae strains have emerged over the past decade at an alarming rate. The molecular mechanism of trimethoprim resistance was investigated in 5 pneumococcal strains isolated in the Washington, DC, area from patients with invasive infections. Cloning and sequencing of the trimethoprim resistance determinant from these pneumococci indicated that an altered chromosome-encoded dihydrofolate reductase (DHFR) was responsible for the observed resistance. Comparison of DHFR sequences from pneumococcal strains with various susceptibilities to trimethoprim, together with site-directed mutagenesis, revealed that substitution of isoleucine-100 with a leucine residue resulted in trimethoprim resistance. Hydrogen bonding between the carbonyl oxygen of isoleucine-100 and the 4-amino group of trimethoprim is proposed to play a critical role in the inhibition of DHFR by trimethoprim. This enzyme-substrate model should facilitate the design of new antibacterial agents with improved activity against S. pneumoniae.

Respiratory syncytial virus immune globulin treatment of RSV lower respiratory tract infection in previously healthy children.

OBJECTIVE: To evaluate the efficacy of high titer respiratory syncytial virus (RSV) immune globulin (RSVIG) in the treatment of previously healthy children hospitalized with proven RSV lower tract infection (LRI). METHOD: Infants and young children /=2. 5 were enrolled. RESULTS: One hundred and one previously healthy children hospitalized with RSV LRI received either 1500 mg/kg of RSVIG (RespiGam, MedImmune Inc, Gaithersburg, MD) or albumin placebo in a randomized, double-blind, placebo-controlled trial. Forty-six RSVIG and 52 recipients of placebo met all eligibility criteria. Demographic characteristics of the two groups were similar. More RSVIG recipients (46% vs 29%) had an SaO2 /=3.0) had 1.6 fewer hospital days and 2.7 days less ICU stays. CONCLUSION: RSVIG infusions seemed safe and generally well tolerated. Although some beneficial effect trends were seen for those with more severe disease who were treated there was no evidence that treatment with RSVIG resulted in reduced hospitalization and reduced ICU stays in all children with RSV disease.

Decreased susceptibility to imipenem among penicillin-resistant Streptococcus pneumoniae.

We assessed the antimicrobial susceptibilities of 59 penicillin-intermediate or penicillin-resistant pneumococci. All strains were susceptible to vancomycin and rifampicin. The frequency of strains with decreased susceptibility to cefotaxime, chloramphenicol, imipenem and meropenem was 15, 31, 47 and 49% respectively. The high percentage of penicillin-intermediate or penicillin-resistant Streptococcus pneumoniae with decreased susceptibility to third-generation cephalosporins, chloramphenicol and carbapenems limits the therapeutic options for the treatment of invasive pneumococcal infections and particularly of meningitis.

Respiratory syncytial virus (RSV) immune globulin intravenous therapy for RSV lower respiratory tract infection in infants and young children at high risk for severe RSV infections: Respiratory Syncytial Virus Immune Globulin Study Group.

OBJECTIVES: To evaluate the efficacy of high-titer intravenous respiratory syncytial virus immune globulin (RSVIG) in the treatment of children at high risk for severe RSV infection who were hospitalized with proven RSV. METHODS: Infants and young children younger than 2 years with bronchopulmonary dysplasia, chronic lung disease, congenital heart disease, or prematurity (<32 weeks' gestational age), hospitalized with a history of lower respiratory tract infection (LRI) of less than 4 days, were enrolled in this study. Patients were randomized in a blinded fashion to receive either 1500 mg/kg RSVIG or placebo in equal volumes. They were evaluated daily for safety and respiratory scores and for RSV nasal shedding. RESULTS: One hundred seven high-risk children were randomized--54 in the RSVIG group and 53 in the placebo group. Of these children, 51 in each group were considered evaluable. Children with pulmonary disease, congenital heart disease, or prematurity were equally distributed between the two treatment groups. However, two important differences were found in baseline variables between the two groups: there were more patients in the placebo group who had histories of previous LRI and there was a trend toward more severe disease at study entry in the RSVIG group. This was manifested by a higher entry respiratory score in the RSVIG group than in the placebo group (3.4 +/- 0.2 vs 3.1 +/- .01). A higher proportion of children in the RSVIG group (47%) than in the placebo group (28%) required intensive care at entry and mechanical ventilation at study entry (31% RSVIG-treated vs 18% placebo-treated patients). No significant difference was found between groups in the mean unadjusted duration of hospitalization (RSVIG group, 9.10 +/- 1.18 days; control group, 8.17 +/- 1.08 days). When the mean was adjusted for entry respiratory score, likewise, no difference was observed between each group (8.41 +/- 0.97 vs 8.89 +/- .99 days). The lack of efficacy observed in the study primary endpoint was observed in all diagnostic groups. No differences between the RSVIG and placebo groups were observed in the following secondary endpoints: duration of intensive care unit stay, duration of intensive care unit stay for RSV, mechanical ventilation, or supplemental oxygen. No significant differences in adverse events were reported in the RSVIG group (16 children) when compared with the control group (10 children). CONCLUSION: RSVIG treatment was safe but not efficacious in the treatment of children with bronchopulmonary dysplasia, congenital heart disease, or premature gestation who were hospitalized with RSV LRI.

Increasing incidence of penicillin- and ampicillin-resistant middle ear pathogens.

During a 13-month period ending in January, 1995, we obtained 159 samples of middle ear exudate through tympanocentesis (n = 155) or acute spontaneous otorrhea (n = 4) from 151 children enrolled in therapeutic trials of acute otitis media in a pediatric practice in Northern Virginia. Their ages ranged from < 1 to > 6 years of age (mean, 35 months; median, 22 months). Precise diagnostic criteria for acute otitis media always included bulging outward of all or part of the eardrum, opacification of the eardrum regardless of color and impaired mobility to positive and negative pressure via the pneumatic otoscope. Bacterial pathogens were isolated from middle ear fluid in 95% of these children: Streptococcus pneumoniae was recovered from 61 (37%); Haemophilus influenzae from 45 (27%); Moraxella catarrhalis from 41 (25%); Group A streptococcus from 6 (4%); Staphylococcus aureus from 4 (2%); and no growth or microbes of uncertain significance from 8 (5%). Six of the patients had mixed bacterial cultures; 2 of the 6 had at least one ampicillin-resistant bacteria, and a third had 2 ampicillin-resistant bacteria. Eight patients who failed to improve with antimicrobial treatment had a second tympanocentesis performed or developed spontaneous drainage; on that follow-up culture 3 of 8 cultures had different microorganisms; and 5 of the 8 bacterial specimens were resistant to ampicillin or penicillin. Twenty-one percent of the S. pneumoniae strains recovered from the middle ear were resistant to penicillin. Sixty-two percent of the H. influenzae and 98% of the M. catarrhalis isolates were resistant to ampicillin. Overall bacteria resistant to penicillin or ampicillin were recovered in 54% of middle ear fluid from 46 patients who had received a beta-lactam antibiotic in the preceding month as well as in 57% of middle ear fluids from 105 patients who had not. The empiric use of amoxicillin for treatment of acute otitis media should be reexamined in our community particularly in those who appear ill, have a high fever or have severe unremitting otalgia.

Safety and bioequivalency of three formulations of respiratory syncytial virus-enriched immunoglobulin.

Respiratory syncytial virus (RSV) causes serious illness (lower respiratory illness) in preterm infants. RSV antibody-enriched immunoglobulin (RSVIG) that was lyophilized (LYO) protected against RSV lower respiratory illness. The Food and Drug Administration now requires an additional viral inactivation step (VI). We compared LYO, LYO-VI, and a more convenient liquid RSVIG (LIQ-VI) in 30 preterm infants (median age, 7 months; median weight, 5.4 kg). Infants were randomized to receive LYO (n = 10), LYO-VI (n = 10), or LIQ-VI (n = 10) in monthly infusions of 750 mg/kg of body weight per dose (December to March). Children were monitored closely for adverse reactions to RSVIG and for RSV illness.

Streptococcus pneumoniae resistant to penicillin: incidence and potential therapeutic options.

Streptococcus pneumoniae was recovered from 12 (50%) samples of middle ear fluid of 24 consecutive patients with AOME and in mixed culture of middle ear pathogens from one (4%) additional specimen. Two (15.3%) isolates had intermediate resistance to penicillin (minimal inhibitory concentration (MIC) 0.125 and 1.0 micrograms/mL). The antimicrobial susceptibility to various antimicrobials of 30 S pneumoniae strains recovered from patients seen in the last 12 months was also determined. One of the patients with AOME developed bacteremia that resolved uneventfully, whereas the other developed meningitis. MIC90 was determined from penicillin (2 micrograms/mL), erythromycin (> 32 micrograms/mL), cefaclor (32 micrograms/mL), loracarbef (> or = 64 micrograms/mL), cefixime (16 micrograms/mL), ceftibuten (> 64 micrograms/mL), chloramphenicol (16 micrograms/mL), cefpodoxime (4 micrograms/mL), ciprofloxacin (2 micrograms/mL), cephalexin (> or = micrograms/mL), augmentin (2 micrograms/mL), cefprozil (8 micrograms/mL), clindamycin (64 micrograms/mL), TMP-SXT (> 64 micrograms/mL), clarithromycin (32 micrograms/mL), rifampin (0.06 micrograms/mL), cefuroxime (2 micrograms/mL), cefotaxime (0.25 micrograms/mL), vancomycin (0.25 micrograms/mL), and imipenem (0.5 micrograms/mL). Cefprozil, vancomycin, and rifampin inhibited all strains, whereas cefpodoxime, cefuroxime, clindamycin, and clarithromycin exhibited very good activity.

Penicillin-resistant pneumococci from pediatric patients in the Washington, DC, area.

OBJECTIVE: To assess the prevalence and antimicrobial susceptibility of penicillin-resistant pneumococci (PRP) isolated from patients in a pediatric hospital. METHODS: All (108) isolates of Streptococcus pneumoniae recovered from usually sterile body sites between June 1, 1992, and May 31, 1993, were screened for susceptibility to penicillin by the E-test method. Minimum inhibitory concentrations of penicillin and other antibiotics were also determined by an agar dilution method for 10 PRP and 22 penicillin-susceptible strains. RESULTS: Fourteen isolates (12.9%) were PRP by the E-test; nine of these (8.3%) were intermediately resistant and five (4.6%) were highly resistant. All strains were sensitive to rifampin and vancomycin. Increased frequency of resistance to oral and parenteral cephalosporins and carbapenems was found among PRP; for most of these antibiotics, resistance exceeded 40% of the PRP. In addition, 20% of the PRP were resistant to macrolides and all penicillin-susceptible and PRP were resistant to a combination of trimethoprim and sulfamethoxazole. CONCLUSIONS: The decreased susceptibility to oral and parenteral cephalosporins, macrolides, a combination of trimethoprim and sulfamethoxazole, and carbapenems creates a significant problem in the treatment of pneumococcal infections in both ambulatory and hospitalized patients.