Macrolide resistance among invasive Streptococcus pneumoniae isolates.

CONTEXT: Macrolide antibiotics, including erythromycin, clarithromycin, and azithromycin, are the mainstays of empirical pneumonia therapy. Macrolide resistance among Streptococcus pneumoniae, the most common cause of community-acquired pneumonia, is increasing in the United States. Whether resistance is a significant problem or whether macrolides remain useful for treatment of most resistant strains is unknown. OBJECTIVE: To examine the epidemiology of macrolide-resistant pneumococci in the United States. DESIGN AND SETTING: Analysis of 15 481 invasive isolates from 1995 to 1999 collected by the Centers for Disease Control and Prevention's Active Bacterial Core surveillance system in 8 states. MAIN OUTCOME MEASURES: Trends in macrolide use (1993-1999) and resistance and factors associated with resistance, including examination of 2 subtypes, the M phenotype, associated with moderate minimum inhibitory concentrations (MICs), and the MLS(B) phenotype, associated with high MICs and clindamycin resistance. RESULTS: From 1993 to 1999, macrolide use increased 13%; macrolide use increased 320% among children younger than 5 years. Macrolide resistance increased from 10.6% in 1995 to 20.4% in 1999. M phenotype isolates increased from 7.4% to 16.5% (P<.001), while the proportion with the MLS(B) phenotype was stable (3%-4%). The median erythromycin MIC (MIC(50)) of M phenotype isolates increased from 4 microg/mL to 8 microg/mL. In 1999, M phenotype strains were more often from children than persons 5 years or older (25.2% vs 12.6%; P<.001) and from whites than blacks (19.3% vs 11.2%; P<.001). CONCLUSIONS: In the setting of increasing macrolide use, pneumococcal resistance has become common. Most resistant strains have MICs in the range in which treatment failures have been reported. Further study and surveillance are critical to understanding the clinical implications of our findings.

Risk factors for positive mantoux tuberculin skin tests in children in San Diego, California: evidence for boosting and possible foodborne transmission.

OBJECTIVES: Source case finding in San Diego, California, rarely detects the source for children with tuberculosis (TB) infection or disease. One third of all pediatric TB isolates in San Diego are Mycobacterium bovis, a strain associated with raw dairy products. This study was conducted to determine risk factors for TB infection in San Diego. DESIGN: Case-control study of children /=10 mm) Mantoux skin test (TST) were matched by age to 1 to 2 children with negative TST from the same clinic. We assessed risk factors for TB infection through parental interview and chart review. RESULTS: A total of 62 cases and 97 controls were enrolled. Eleven cases and 25 controls were excluded from analysis because of previous positive skin tests. Compared with controls, cases were more likely to have received BCG vaccine (73% vs 7%, odds ratio [OR] 44), to be foreign born (35% vs 11%, OR 4.3), and to have eaten raw milk or cheese (21% vs 8%, OR 3.76). The median time between the most recent previous TST and the current test was 12 months for cases and 25 months for controls. Other factors associated with a positive TST included foreign travel, staying in a home while out of the country, and having a relative with a positive TST. There was no association between contact with a known TB case. In a multivariable model, receipt of BCG, contact with a relative with a positive TST, and having a previous TST within the past year were independently associated with TB infection. CONCLUSIONS: We identified several new or reemerging associations with positive TST including cross border travel, staying in a foreign home, and eating raw dairy products. The strong associations with BCG receipt and more recent previous TST may represent falsely positive reactions, booster phenomena, or may be markers for a population that is truly at greater risk for TB infection. Unlike studies conducted in nonborder areas, we found no association between positive TB skin tests and contact with a TB case or a foreign visitor. Efforts to control pediatric TB in San Diego need to address local risk factors including consumption of unpasteurized dairy products and cross-border travel. The interpretation of a positive TST in a young child in San Diego who has received BCG is problematic.

Surveillance for meningococcal disease and strategies for use of conjugate meningococcal vaccines in the United States.

BACKGROUND: Neisseria meningitidis is a leading cause of bacterial meningitis in US; new capsular type-specific conjugate vaccines offer an opportunity for improved control of meningococcal disease. We evaluated the relative burdens of invasive meningococcal disease in US and examined the projected impact of various meningococcal conjugate vaccination strategies on rates of meningococcal disease. METHODS: Meningococcal disease incidence rates were determined from active, population-based surveillance in selected US areas. Models were created to determine impact of vaccination of infants, toddlers, adolescents or college students with meningococcal conjugate vaccines, with assumptions for vaccine coverage, efficacy and duration of protection. Although we examined possible conjugate vaccine formulations including serogroups A, C, Y and W-135, the final vaccine impact analysis excluded serogroups A and W-135. Outcome measures were cumulative meningococcal disease incidence, and incidence 10 years after initiating vaccination among 0-22-year-olds. RESULTS: In models of serogroup C+Y meningococcal conjugate vaccination of infants, toddlers and adolescents, the cumulative incidence of meningococcal disease was reduced by 54, 48 and 25%, respectively; the toddler strategy had the greatest impact per dose. After 10 years of routine meningococcal conjugate vaccination, meningococcal disease could be reduced by 50% and deaths by 64%. CONCLUSIONS: Use of meningococcal conjugate vaccine could markedly reduce meningococcal disease incidence. Our data, along with vaccine formulation and vaccination program considerations, will be important in determining the optimal choice of vaccination strategy.

Comparison of two commercial microimmunofluorescence kits and an enzyme immunoassay kit for detection of serum immunoglobulin G antibodies to Chlamydia pneumoniae.

We compared the MRL and the Labsystems Chlamydia pneumoniae microimmunofluorescence (MIF) immunoglobulin G (IgG) kits and the Labsystems enzyme immunoassay (EIA) kit in a blinded study of 83 serum samples in which we evaluated titers, cross-reactivity to other species, and reproducibility. There was no statistically significant difference between the MRL and the Labsystems MIF kits in the endpoint titers of IgG antibody to C. pneumoniae. The correlation between the results obtained with these two MIF kits was excellent (r = 0.95; P = 0.001). The cross-reactivity of the C. pneumoniae-positive sera with C. trachomatis- and C. psittaci-positive sera was assessed for each MIF kit. For C. pneumoniae-positive sera with titers of > or =32, the Labsystems MIF kit exhibited more cross-reactivity to C. psittaci than the MRL kit did. The values obtained with the Labsystems EIA kit represented single dilutions of serum specimens expressed as enzymeimmuno units on a continuous scale. The results obtained with the Labsystems EIA kit correlated moderately well with those obtained with each MIF kit when they were compared for their abilities to detect IgG antibodies to C. pneumoniae (for the MRL MIF kit, r = 0.79 [P = 0.001]; for the Labsystems MIF kit, r = 0.78 [P = 0.001]). The results obtained with the commercial MRL and Labsystems MIF kits and the Labsystems EIA kit tested were reproducible; and the kits were standardized, had quality control reagents, and are suitable for detection of C. pneumoniae antibodies in serum and for use in interlaboratory studies. Validation of the use of these kits for clinical diagnosis still needs further evaluation.

Forty years and four surveys: how does our measuring measure up?

OBJECTIVE: This article reviews four surveys methodologies that have been used over the past 40 years to assess immunization rates in young children in the United States. These methods include three national surveys: (1) United States Immunization Survey (1959-1985), which was first a household and then a telephone survey; (2) National Health Interview Survey (1991-present), which interviews people in their homes; and (3) National Immunization Survey (1994-present), a random-digit-dialing telephone survey. In addition, a series of retrospective school record surveys that used standard sampling and assessment methodologies were conducted nationally during 4 school years September 1990-May 1991. METHODS: Federal publications, National Immunization Conference proceedings, and Centers for Disease Control and Prevention (CDC) internal reports regarding national immunization surveys were reviewed. The methodology used in each survey is presented, and selected examples of previously tabulated results are presented. CONCLUSIONS: The assessment of immunization coverage in American preschool children requires ongoing commitment and survey expertise. Over the past 40 years the CDC's efforts to determine vaccination coverage in young children has evolved from the comparatively simple United States Immunization Survey to the current National Immunization Survey that utilizes sophisticated statistical and survey techniques to obtain the most-accurate results yet available.

Epidemiology of invasive Streptococcus pneumoniae infections in the United States, 1995-1998: Opportunities for prevention in the conjugate vaccine era.

CONTEXT: Pneumococcal polysaccharide vaccine is recommended for elderly persons and adults with certain chronic illnesses. Additionally, a recently licensed pneumococcal 7-valent conjugate vaccine has been recommended for use in young children and could dramatically change the epidemiology of pneumococcal disease. OBJECTIVES: To assess pneumococcal disease burden in the United States, estimate the potential impact of new vaccines, and identify gaps in vaccine recommendations. DESIGN AND SETTING: Analysis of data from the Active Bacterial Core Surveillance (ABCs)/Emerging Infections Program Network, an active, population-based system in 9 states. PATIENTS: A total of 15 860 cases of invasive pneumococcal disease occurring between January 1, 1995, and December 31, 1998. MAIN OUTCOME MEASURES: Age- and race-specific pneumoccocal disease incidence rates per 100 000 persons, case-fatality rates, and vaccine preventability. RESULTS: In 1998, overall incidence was 23.2 cases per 100 000, corresponding to an estimated 62 840 cases in the United States. Incidence was highest among children younger than 2 years (166.9) and adults aged 65 years or older (59.7). Incidence among blacks was 2.6 times higher than among whites (95% confidence interval [CI], 2.4-2.8). Overall, 28.6% of case-patients were at least 65 years old and 85.9% of cases in this age group were due to serotypes included in the 23-valent polysaccharide vaccine; 19.3% of case-patients were younger than 2 years and 82.2% of cases in this age group were due to serotypes included in the 7-valent conjugate vaccine. Among patients aged 2 to 64 years, 50.6% had a vaccine indication as defined by the Advisory Committee on Immunization Practices (ACIP). The case-fatality rate among patients aged 18 to 64 years with an ACIP indication was 12.1% compared with 5.4% for those without an indication (relative risk, 2.2; 95% CI, 1.7-2.9). CONCLUSIONS: Young children, elderly persons, and black persons of all ages are disproportionately affected by invasive pneumococcal disease. Current ACIP recommendations do not address a subset of persons aged 18 to 64 years but do include those at highest risk for death from invasive pneumococcal disease.

Azithromycin prophylaxis during a hospital outbreak of Mycoplasma pneumoniae pneumonia.

Outbreaks of Mycoplasma pneumoniae (MP) in closed communities can have a high attack rate and can last several months. Azithromycin chemoprophylaxis has not been evaluated as a means of limiting transmission. This randomized, double-blinded placebo-controlled trial of azithromycin was conducted among asymptomatic hospital employees during an MP outbreak. Oropharyngeal swabs were obtained for detection of MP by polymerase chain reaction, and questionnaires were administered to assess clinical illness. Of the 147 employees who were enrolled, 73 received azithromycin and 74 received placebo. Carriage was similar within and between groups at weeks 1 and 6 (9.6% vs. 6.7% and 10.3% vs. 13.2%, respectively). Four episodes of clinically significant respiratory illness occurred in the azithromycin group versus 16 episodes in the placebo group (protective efficacy, 75%; 95% confidence interval, 28%-91%). Use of azithromycin prophylaxis in asymptomatic persons during an MP outbreak in a closed setting may be of value in reducing clinical illness.

National Immunization Survey: the methodology of a vaccination surveillance system.

The National Immunization Survey (NIS) was designed to measure vaccination coverage estimates for the US, the 50 states, and selected urban areas for children ages 19-35 months. The NIS includes a random-digit-dialed telephone survey and a provider record check study. Data are weighted to account for the sample design and to reduce nonresponse and non-coverage biases in order to improve vaccination coverage estimates. Adjustments are made for biases resulting from nonresponse and nontelephone households, and estimation procedures are used to reduce measurement bias. The NIS coverage estimates represent all US children, not just children living in households with telephones. NIS estimates are highly comparable to vaccination estimates derived from the National Health Interview Survey. The NIS allows comparisons between states and urban areas over time and is used to evaluate current and new vaccination strategies.

Mortality from pneumonia in children in the United States, 1939 through 1996.

BACKGROUND AND METHODS: Pneumonia remains an important cause of childhood deaths throughout the world, but in developed countries, the mortality rate is decreasing. We reviewed death records for children in the United States from 1939 through 1996. A plot of the annual rates of change in the number of deaths from pneumonia was used to generate hypotheses about the influence of various events and interventions. We used data from the National Hospital Discharge Survey, the Medicaid program, and published reports to test these hypotheses. RESULTS: During the 58-year study period, the number of children who died from pneumonia declined by 97 percent, from 24,637 in 1939 to 800 in 1996. During the same period, the rate of mortality from other causes declined by 82 percent. There were steep declines in the mortality rates for pneumonia from 1944 to 1950, although the rate increased among older children in 1957, and there were sustained declines in all age groups from 1966 to 1982. From 1966 to 1982, the mortality declined by an average of 13.0 percent annually, and these decreases coincided with increases in the proportion of poor children covered by Medicaid, increases in rates of hospitalization for pneumonia, a narrowing of the gap between the mortality rate for black children and the rate for white children, and a convergence between the mortality rate in the South and the rates in the other three census regions. CONCLUSIONS: Since 1939, the rate of mortality from pneumonia in children in the United States has declined markedly. We hypothesize that the steep declines in the late 1940s are attributable to the use of penicillin, that the peak in 1957 was due to the influenza A pandemic, and that the sustained decline from 1966 through 1982 may be attributable in part to improved access to medical care for poor children.

Increasing prevalence of multidrug-resistant Streptococcus pneumoniae in the United States.

BACKGROUND: The emergence of drug-resistant strains of bacteria has complicated treatment decisions and may lead to treatment failures. METHODS: We examined data on invasive pneumococcal disease in patients identified from 1995 to 1998 in the Active Bacterial Core Surveillance program of the Centers for Disease Control and Prevention. Pneumococci that had a high level of resistance or had intermediate resistance according to the definitions of the National Committee for Clinical Laboratory Standards were defined as "resistant" for this analysis. RESULTS: During 1998, 4013 cases of invasive Streptococcus pneumoniae disease were reported (23 cases per 100,000 population); isolates were available for 3475 (87 percent). Overall, 24 percent of isolates from 1998 were resistant to penicillin. The proportion of isolates that were resistant to penicillin was highest in Georgia (33 percent) and Tennessee (35 percent), in children under five years of age (32 percent, vs. 21 percent for persons five or more years of age), and in whites (26 percent, vs. 22 percent for blacks). Penicillin-resistant isolates were more likely than susceptible isolates to have a high level of resistance to other antimicrobial agents. Serotypes included in the 7-valent conjugate and 23-valent pneumococcal polysaccharide vaccines accounted for 78 percent and 88 percent of penicillin-resistant strains, respectively. Between 1995 and 1998 (during which period 12,045 isolates were collected), the proportion of isolates that were resistant to three or more classes of drugs increased from 9 percent to 14 percent; there also were increases in the proportions of isolates that were resistant to penicillin (from 21 percent to 25 percent), cefotaxime (from 10 percent to 15 percent), meropenem (from 10 percent to 16 percent), erythromycin (from 11 percent to 16 percent), and trimethoprim-sulfamethoxazole (from 25 percent to 29 percent). The increases in the frequency of resistance to other antimicrobial agents occurred exclusively among penicillin-resistant isolates. CONCLUSIONS: Multidrug-resistant pneumococci are common and are increasing. Because a limited number of serotypes account for most infections with drug-resistant strains, the new conjugate vaccines offer protection against most drug-resistant strains of S. pneumoniae.

Optimizing culture of Chlamydia pneumoniae by using multiple centrifugations.

Three methods for the recovery of Chlamydia pneumoniae from spiked nasopharyngeal and blood specimens, including extended culture and additional centrifugations, were compared. Additional centrifugations and a 7-day culture time resulted in a 500- to 5, 000-fold increase in the number of detectable inclusion-forming units.

Immunogenicity of high-titre AIK-C or Edmonston-Zagreb vaccines in 3.5-month-old infants, and of medium- or high-titre Edmonston-Zagreb vaccine in 6-month-old infants, in Kinshasa, Zaire.

The effect of measles vaccine potency was evaluated among 485 children aged 6 months, and the effect of vaccine strain was evaluated among 538 children aged 3.5 months, in Kinshasa, Zaire. Children aged 6 months were randomly assigned to receive either high-titre Edmonston-Zagreb (EZ-H), potency 5.7 log10/dose, or medium-titre EZ (EZ-M), potency 4.7 log10/dose, those aged 3.5 months were randomly assigned to receive either AIK-C, potency 5.5 log10/dose, or EZ-H, and were revaccinated with EZ-M vaccine at age 9.5 months. Measles antibodies were measured using the plaque reduction neutralization assay. Among children vaccinated at age 6 months, the seroresponse was significantly higher after EZ-H than EZ-M vaccine, with 92 and 83% seroconverting by 6 months postvaccination and 59 and 40% respectively having antibody titres > 200 mIU. Among children vaccinated at age 3.5 months, only 24% (AIK-C) and 22% (EZ-H) attained antibody titres > or = 200 mIU 6 months postvaccination. After revaccination at age 9.5 months, 81% of children in the AIK-C group and 73% in the EZ-H group had antibody levels > 200 mIU (p = 0.056). A retrospective survey was conducted in January 1993 to determine the mortality experience of vaccine groups, and information was obtained for 94% of the children. A total of 44 deaths (4%) were identified, with no significant differences between groups when stratified by age at vaccination.(ABSTRACT TRUNCATED AT 250 WORDS)

Potential impact on vaccination coverage levels by administering vaccines simultaneously and reducing dropout rates.

BACKGROUND: Retrospective immunization coverage surveys conducted during 1991 and 1992 demonstrated that coverage levels for the routine childhood vaccines by 24 months of age in selected urban areas of the United States ranged from 10% to 52%, far below the US Public Health Service goal of 90%. Therefore, appropriate programmatic changes must be identified and incorporated. METHODS: We analyzed coverage survey data collected from 21 sites to measure the potential impact on coverage levels of implementing selected changes in vaccination practices. In a multistaged cluster survey design, school health records of kindergarten or first-grade students were randomly selected and dates of vaccination assessed. We evaluated changes in the vaccination practices, such as eliminating missed opportunities for simultaneous administration of vaccines and ensuring that children initiated the vaccination series on time (ie, by 3 months of age). We then calculated potential increases in coverage levels for a best-case scenario. RESULTS: From 77% to 96% of all children in the 21 sites had received at least one vaccination by their first birthday. Children were 2.3 to 17 times more likely to be up to date on their vaccinations by 24 months of age if they were up to date at 3 months of age. Each child had many opportunities for the simultaneous administration of diphtheria and tetanus toxoids and pertussis (DTP) vaccine, oral polio vaccine (OPV), and measles-mumps-rubella (MMR) vaccine that, if used appropriately, could have potentially raised coverage levels by 12% to 22% (median, 17%). The highest coverage levels could have been attained if all children had started the series on time and if advantage had been taken of all opportunities for simultaneous vaccination. Coverage levels for four doses of DTP vaccine, three doses of OPV, and one dose of MMR vaccine would have increased from a baseline of 10% to 52% to levels of 54% to 83%. CONCLUSIONS: Although the majority of children received a vaccination by their first birthday, the coverage level at 24 months of age was low. Tracking systems are needed to ensure that children do not drop out of the system once they have begun the vaccination series. In addition, all children who are late in beginning their vaccination series are at increased risk of not completing the recommended vaccination series on time, and these children need intensive follow-up and recall efforts. Also, providers need to administer all needed vaccines simultaneously.

Low vaccination levels of US preschool and school-age children. Retrospective assessments of vaccination coverage, 1991-1992.

OBJECTIVE: To obtain estimates on (1) the percentage of children who were up-to-date on the recommended childhood vaccination series, (2) the percentage of children who were age-appropriately immunized, and (3) coverage levels by individual vaccines. DESIGN: Vaccination levels were estimated by conducting retrospective immunization coverage surveys of the school health records of children entering kindergarten or first grade in the 1990-1991 or 1991-1992 school year. A multistage cluster survey design was used. SETTING: Survey sites were selected from among the 60 largest urban areas in the United States. One small city and one rural area were selected for comparison. RESULTS: By their second birthday, 11% to 58% (median, 44%) of the children were fully vaccinated. Stricter measurement criteria lowered coverage levels further. Completed series levels at school entry were 71% to 96% (median, 87%). CONCLUSIONS: Vaccination levels at the second birthday were far below the goal for the year 2000. All health providers need to administer vaccines according to the recommended schedule.

Outbreaks in highly vaccinated populations: implications for studies of vaccine performance.

Most of the factors associated with the failure of a vaccination to provide protective immunity are not distributed uniformly or randomly within populations. This paper explores the extent to which a nonrandom distribution of vaccination failures and the selection of exceptional situations for investigation may influence estimates of vaccine performance. The authors show that outbreak investigations will tend to underestimate vaccination efficacy, and that the extent of underestimation will be related directly to the size of the epidemic triggering an investigation, the vaccination coverage in the community, and the extent of clustering of vaccination failures in the population; it will be related inversely to the size of and contact intensity within the investigated community. These potential sources of bias are not the only problems that arise in estimating vaccine efficacy, but they should be taken into consideration when analyzing and interpreting outbreak situations. The fact that outbreak investigations carried out within the United States during the past decade have provided estimates of measles vaccination efficacy on the order of 95% is consistent with a somewhat higher overall "true" efficacy of current vaccines and procedures in the total population. It is important to understand better the frequency, distribution, and risk factors for vaccination failures in populations.

Paralytic poliomyelitis in Oman: association between regional differences in attack rate and variations in antibody responses to oral poliovirus vaccine.

Variation in attack rates of paralytic disease by region during the 1988-1989 epidemic of type 1 poliomyelitis in Oman provided the stimulus to test the hypothesis that these observations were due to regional differences in the response of infants to trivalent oral poliovirus vaccine (OPV). Seroprevalence studies of 394 children born during the outbreak were conducted in six different regions of Oman and in two socioeconomic status (SES) groups in the capital city of Muscat; a seroconversion study was also carried out in 105 infants born after the outbreak. Seroprevalence rates by region after receipt of at least three doses of OPV ranged from 90% to 100% (median 94%) to poliovirus type 1, and from 86% to 100% (median 97%) to type 2, and from 47% to 79% (median 72%) to type 3, with the lowest rates observed in regions with the highest incidence of type 1 paralytic disease. In Muscat, seroprevalence rates were also significantly lower in low versus high SES groups (type 1: 84% versus 98%, respectively [P = 0.006]; type 3: 59% versus 86%, respectively [P = 0.001]). In the seroconversion study conducted after the outbreak, 89%, 100% and 50% of infants had detectable antibodies to types 1, 2, and 3, respectively, after four doses of OPV. Low responses to type 3 were also associated with the occurrence of sporadic cases of type 3 poliomyelitis in 1991, in spite of high rates of coverage with at least four doses of OPV (> 96%) throughout the country.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunogenicity of high-titer Edmonston-Zagreb measles vaccine in human immunodeficiency virus-infected children in Kinshasa, Zaire.

The response to Edmonston-Zagreb vaccine (titer, 5.4 log10 pfu) was evaluated among children in a study of perinatal transmission of human immunodeficiency virus (HIV) in Kinshasa. Acute postvaccination adverse events were monitored for 49 HIV-infected and 376 non-HIV-infected infants, and measles antibody responses were assessed by ELISA for 34 HIV-infected and 255 non-HIV-infected infants. There was no increase in the incidence of common symptoms 7-10 days after vaccination. HIV-infected infants were more likely to have detectable prevaccination measles antibody, and seroconversion after vaccination was somewhat lower in HIV-infected (76.5%) than non-HIV-infected infants (85.5%). Seroconversion rates did not differ among children with or without rhinitis or fever at vaccination. High-titer Edmonston-Zagreb vaccine given at 6 months of age has the potential to provide earlier protection against measles; however, this vaccine is no longer recommended for routine use, and two doses of standard-titer vaccines remains the preferred option for measles vaccination of HIV-infected infants.