Active bacterial core surveillance of the emerging infections program network.

Active Bacterial Core surveillance (ABCs) is a collaboration between the Centers for Disease Control and Prevention and several state health departments and universities participating in the Emerging Infections Program Network. ABCs conducts population-based active surveillance, collects isolates, and performs studies of invasive disease caused by Streptococcus pneumoniae, group A and group B Streptococcus, Neisseria meningitidis, and Haemophilus influenzae for a population of 17 to 30 million. These pathogens caused an estimated 97,000 invasive cases, resulting in 10,000 deaths in the United States in 1998. Incidence rates of these pathogens are described. During 1998, 25% of invasive pneumococcal infections in ABCs areas were not susceptible to penicillin, and 13.3% were not susceptible to three classes of antibiotics. In 1998, early-onset group B streptococcal disease had declined by 65% over the previous 6 years. More information on ABCs is available at www.cdc.gov/ncidod/dbmd/abcs. ABCs specimens will soon be available to researchers through an archive.

Nosocomial transmission of Mycobacterium tuberculosis from an extrapulmonary site.

OBJECTIVE: To assess the extent of nosocomial transmission and risk factors associated with tuberculin skin test (TST) conversions among healthcare workers (HCWs) exposed to a patient with genitourinary Mycobacterium tuberculosis. DESIGN: Retrospective cohort study of exposed HCWs. SETTING: A 275-bed community hospital in Middle Tennessee. PARTICIPANTS: A total of 128 exposed HCWs and the index patient, who required drainage of a prostatic abscess and bilateral orchiectomy and expired after a 27-day hospitalization. Disseminated tuberculosis was diagnosed at autopsy. METHODS: Contact tracing was performed on exposed HCWs. Logistic regression was used to identify independent risk factors associated with TST conversion. RESULTS: A total of 128 HCWs were exposed to the index patient. There was no evidence of active pulmonary tuberculosis throughout the patient's hospitalization; TST conversions occurred only among HCWs who were exposed to the patient during or after his surgical procedures. A total of 12 (13%) of 95 exposed HCWs who were previously nonreactive had newly positive TST: 6 of 28 nurses, 3 of 3 autopsy personnel, 2 of 17 respiratory therapists, and 1 of 12 surgical staff. By logistic regression, irrigation or packing of the surgical site was the only independent risk factor associated with TST conversion among nurses (odds ratio, 9; 95% confidence interval, 1.2-67; P=.03). CONCLUSION: Manipulation of infected tissues of the genitourinary tract can result in nosocomial transmission of tuberculosis.

Mortality from invasive pneumococcal pneumonia in the era of antibiotic resistance, 1995-1997.

OBJECTIVES: This study examined epidemiologic factors affecting mortality from pneumococcal pneumonia in 1995 through 1997. METHODS: Persons residing in a surveillance area who had community-acquired pneumonia requiring hospitalization and Streptococcus pneumoniae isolated from a sterile site were included in the analysis. Factors affecting mortality were evaluated in univariate and multivariate analyses. The number of deaths from pneumococcal pneumonia requiring hospitalization in the United States in 1996 was estimated. RESULTS: Of 5837 cases, 12% were fatal. Increased mortality was associated with older age, underlying disease. Asian race, and residence in Toronto/Peel, Ontario. When these factors were controlled for, increased mortality was not associated with resistance to penicillin or cefotaxime. However, when deaths during the first 4 hospital days were excluded, mortality was significantly associated with penicillin minimum inhibitory concentrations of 4.0 or higher and cefotaxime minimum inhibitory concentrations of 2.0 or higher. In 1996, about 7000 to 12,500 deaths occurred in the United States from pneumococcal pneumonia requiring hospitalization. CONCLUSIONS: Older age and underlying disease remain the most important factors influencing death from pneumococcal pneumonia. Mortality was not elevated in most infections with beta-lactam-resistant pneumococci.

Group B streptococcal disease in the era of intrapartum antibiotic prophylaxis.

BACKGROUND: Group B streptococcal infections are a leading cause of neonatal mortality, and they also affect pregnant women and the elderly. Many cases of the disease in newborns can be prevented by the administration of prophylactic intrapartum antibiotics. In the 1990s, prevention efforts increased. In 1996, consensus guidelines recommended use of either a risk-based or a screening-based approach to identify candidates for intrapartum antibiotics. To assess the effects of the preventive efforts, we analyzed trends in the incidence of group B streptococcal disease from 1993 to 1998. METHODS: Active, population-based surveillance was conducted in selected counties of eight states. A case was defined by the isolation of group B streptococci from a normally sterile site. Census and live-birth data were used to calculate the race-specific incidence of disease; national projections were adjusted for race. RESULTS: Disease in infants less than seven days old accounted for 20 percent of all 7867 group B streptococcal infections. The incidence of early-onset neonatal infections decreased by 65 percent, from 1.7 per 1000 live births in 1993 to 0.6 per 1000 in 1998. The excess incidence of early-onset disease in black infants, as compared with white infants, decreased by 75 percent. Projecting our findings to the entire United States, we estimate that 3900 early-onset infections and 200 neonatal deaths were prevented in 1998 by the use of intrapartum antibiotics. Among pregnant girls and women, the incidence of invasive group B streptococcal disease declined by 21 percent. The incidence among nonpregnant adults did not decline. CONCLUSIONS: Over a six-year period, there has been a substantial decline in the incidence of group B streptococcal disease in newborns, including a major reduction in the excess incidence of these infections in black infants. These improvements coincide with the efforts to prevent perinatal disease by the wider use of prophylactic intrapartum antibiotics.

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.

Expression of group IA phospholipase A2 in Pichia pastoris: identification of a phosphatidylcholine activator site using site-directed mutagenesis.

Site-directed mutants of the group IA phospholipase A(2) from cobra venom were constructed and expressed in the methylotrophic yeast Pichia pastoris to probe for the proposed phosphatidylcholine (PC) activator site. Previous crystallographic and molecular modeling studies have identified two regions of the enzyme as likely candidates for this site. Residues Glu-55, Trp-61, Tyr-63, Phe-64, and Lys-65 were mutated to test the site advanced by Ortiz et al. [(1992) Biochemistry 31, 2887-2896] while Asp-23 and Arg-30 were mutated to assess the site proposed by Segelke et al. [(1998) J. Mol. Biol. 279, 223-232]. Expressed enzymes were purified by affinity chromatography and analyzed by SDS-PAGE, Western blotting, electrospray ionization mass spectroscopy, and circular dichroism. Both phospholipid headgroup specificity and rates of hydrolysis on monomeric PC substrates were determined and found to be similar for native, wild-type, and all of the mutant enzymes. These results suggest that all of the expressed enzymes were properly folded and contained functional catalytic sites. Mutations of the aromatic residues in the Ortiz site generally had little effect on PC activation, arguing against the importance of this region of the enzyme for PC activation; however, these aromatic amino acids appeared to be important for interfacial activation. In contrast, the D23N mutant in the Segelke site reduced PC activation by 10-fold without affecting activity toward micellar phosphatidylethanolamine substrates. Similar results were found with the D23N/R30M double mutant, suggesting that this region is critical for PC activation. These results provide evidence for the Segelke site as a PC activator site that is distinct from the catalytic site.

The changing epidemiology of meningococcal disease in the United States, 1992-1996.

New meningococcal vaccines are undergoing clinical trials, and changes in the epidemiologic features of meningococcal disease will affect their use. Active laboratory-based, population-based US surveillance for meningococcal disease during 1992-1996 was used to project that 2400 cases of meningococcal disease occurred annually. Incidence was highest in infants; however, 32% of cases occurred in persons >/=30 years of age. Serogroup C caused 35% of cases; serogroup B, 32%; and serogroup Y, 26%. Increasing age (relative risk [RR], 1.01 per year), having an isolate obtained from blood (RR, 4.5), and serogroup C (RR, 1.6) were associated with increased case fatality. Among serogroup B isolates, the most commonly expressed serosubtype was P1.15; 68% of isolates expressed 1 of the 6 most common serosubtypes. Compared with cases occurring in previous years, recent cases are more likely to be caused by serogroup Y and to occur among older age groups. Ongoing surveillance is necessary to determine the stability of serogroup and serosubtype distribution.

Group V phospholipase A(2)-dependent induction of cyclooxygenase-2 in macrophages.

When exposed for prolonged periods of time (up to 20 h) to bacterial lipopolysaccharide (LPS) murine P388D(1) macrophages exhibit a delayed prostaglandin biosynthetic response that is entirely mediated by cyclooxygenase-2 (COX-2). Both the constitutive Group IV cytosolic phospholipase A(2) (cPLA(2)) and the inducible Group V secretory phospholipase A(2) (sPLA(2)) are involved in the cyclooxygenase-2-dependent generation of prostaglandins in response to LPS. Using the selective sPLA(2) inhibitor 3-(3-acetamide-1-benzyl-2-ethylindolyl-5-oxy)propane sulfonic acid (LY311727) and an antisense oligonucleotide specific for Group V sPLA(2), we found that induction of COX-2 expression is strikingly dependent on Group V sPLA(2), which was further confirmed by experiments in which exogenous Group V sPLA(2) was added to the cells. Exogenous Group V sPLA(2) was able to induce significant arachidonate mobilization on its own and to induce expression of the COX-2. None of these effects was observed if inactive Group V sPLA(2) was utilized, implying that enzyme activity is crucial for these effects to take place. Therefore, not only delayed prostaglandin production but also COX-2 gene induction are dependent on a catalytically active Group V sPLA(2). COX-2 expression was also found to be blunted by the Group IV cPLA(2) inhibitor methyl arachidonyl fluorophosphonate, which we have previously found to block Group V sPLA(2) induction as well. Collectively, the results support a model whereby Group IV cPLA(2) activation regulates the expression of Group V sPLA(2), which in turn is responsible for delayed prostaglandin production by regulating COX-2 expression.

Risk factors for invasive pneumococcal disease in children: a population-based case-control study in North America.

OBJECTIVE: To identify risk factors for invasive pneumococcal disease, including penicillin-resistant infections, among children 2 to 59 months of age. DESIGN: Case-control study. PARTICIPANTS: Patients with invasive pneumococcal infections identified by population-based surveillance (n = 187) and controls identified through random-digit telephone dialing (n = 280). OUTCOME MEASURES: Invasive pneumococcal disease was defined as isolation of Streptococcus pneumoniae from a normally sterile site. Patients 2 to 59 months of age who were residents of one of four active surveillance areas were included. S pneumoniae isolates were tested by broth microdilution. Isolates with a minimum inhibitory concentration to penicillin >/=2 microg/mL were considered resistant. RESULTS: Invasive pneumococcal disease was strongly associated with underlying disease and with day care attendance in the previous 3 months. Among 2- to 11-month-olds, current breastfeeding was associated with a decreased likelihood of invasive pneumococcal disease (odds ratio, 0.27; 95% confidence interval: 0.08, 0.90). Penicillin-resistant infections were independently associated with day care attendance, at least one course of antibiotics, and at least one ear infection in the previous 3 months. CONCLUSIONS: This study shows the association of underlying illnesses, day care attendance, and lack of breastfeeding with risk of invasive pneumococcal disease in children. The association of recent antibiotic use and infection with penicillin-resistant S pneumoniae highlights the need to avoid unnecessary antibiotic use in children.

Long-term efficacy and safety of dronabinol for acquired immunodeficiency syndrome-associated anorexia.

We studied the effects of long-term (12 months) dronabinol in 94 late-stage acquired immunodeficiency syndrome (AIDS) patients (mean CD4 count of 45/mm3) who previously participated in a 6-week study (placebo versus dronabinol). All patients received dronabinol orally-2.5 mg twice daily (90%) or 2.5 mg once daily (10%). Appetite was measured using a visual analogue scale for hunger (VASH). Dronabinol was associated with consistent improvement in mean appetite. Patients previously treated with dronabinol continued to show improvement in VASH (percent change from baseline of 6-week trial: 48.6-76.1% at each month), whereas those previously treated with placebo exhibited substantial improvement in mean appetite, particularly during the initial 4 months of treatment (48.5-69.9%). Thereafter, dronabinol was associated with a VASH change at least twice baseline. Patients tended toward stable body weight for at least 7 months. Adverse events were primarily related to known central nervous system effects of dronabinol. These data support long-term, safe use of dronabinol for anorexia associated with weight loss in patients with AIDS.

Bacterial meningitis in the United States in 1995. Active Surveillance Team.

BACKGROUND: Before the introduction of the conjugate vaccines, Haemophilus influenzae type b was the major cause of bacterial meningitis in the United States, and meningitis was primarily a disease of infants and young children. We describe the epidemiologic features of bacterial meningitis five years after the H. influenzae type b conjugate vaccines were licensed for routine immunization of infants. METHODS: Data were collected from active, population-based surveillance for culture-confirmed meningitis and other invasive bacterial disease during 1995 in laboratories serving all the acute care hospitals in 22 counties of four states (total population, more than 10 million). The rates were compared with those for 1986 obtained by similar surveillance. RESULTS: On the basis of 248 cases of bacterial meningitis in the surveillance areas, the rates of meningitis (per 100,000) for the major pathogens in 1995 were Streptococcus pneumoniae, 1.1; Neisseria meningitidis, 0.6; group B streptococcus, 0.3; Listeria monocytogenes, 0.2; and H. influenzae, 0.2. Group B streptococcus was the predominant pathogen among newborns, N. meningitidis among children 2 to 18 years old, and S. pneumoniae among adults. Pneumococcal meningitis had the highest case fatality rate (21 percent) and in 36 percent of cases was caused by organisms that were not susceptible to penicillin. From these data, we estimate that 5755 cases of bacterial meningitis were caused by these five pathogens in the United States in 1995, as compared with 12,920 cases in 1986, a reduction of 55 percent. The median age of persons with bacterial meningitis increased greatly, from 15 months in 1986 to 25 years in 1995, largely as a result of a 94 percent reduction in the number of cases of H. influenzae meningitis. CONCLUSIONS: Because of the vaccine-related decline in meningitis due to H. influenzae type b, bacterial meningitis in the United States is now a disease predominantly of adults rather than of infants and young children.

Virologic and immunologic benefits of initial combination therapy with zidovudine and zalcitabine or didanosine compared with zidovudine monotherapy. Wellcome Resistance Study Collaborative Group.

A randomized controlled study was done to determine whether initial combination therapy with zidovudine and zalcitabine or zidovudine and didanosine would delay the emergence of zidovudine-resistant virus. Human immunodeficiency virus (HIV)-1-infected patients with <300 CD4 cells/mm3 and <4 weeks of prior zidovudine therapy were randomized to zidovudine, zidovudine plus zalcitabine, or zidovudine plus didanosine. Combination therapy did not delay the emergence of zidovudine-resistant virus isolates. However, combination therapy resulted in a significant increase in CD4 cells through 72 weeks compared with zidovudine monotherapy and a greater and more sustained decline in serum HIV-1 RNA. Although this trial was not designed as a clinical end-point study, patients assigned to zidovudine plus didanosine combination therapy experienced a significant delay in time to first AIDS-defining event or death compared with those assigned to zidovudine monotherapy.

Dronabinol as a treatment for anorexia associated with weight loss in patients with AIDS.

The effects of dronabinol on appetite and weight were evaluated in 139 patients with AIDS-related anorexia and > or = 2.3 kg weight loss in a multi-institutional study. Patients were randomized to receive 2.5 mg dronabinol twice daily or placebo. Patients rated appetite, mood, and nausea by using a 100-mm visual analogue scale 3 days weekly. Efficacy was evaluable in 88 patients. Dronabinol was associated with increased appetite above baseline (38% vs 8% for placebo, P = 0.015), improvement in mood (10% vs -2%, P = 0.06), and decreased nausea (20% vs 7%; P = 0.05). Weight was stable in dronabinol patients, while placebo recipients had a mean loss of 0.4 kg (P = 0.14). Of the dronabinol patients, 22% gained > or = 2 kg, compared with 10.5% of placebo recipients (P = 0.11). Side effects were mostly mild to moderate in severity (euphoria, dizziness, thinking abnormalities); there was no difference in discontinued therapy between dronabinol (8.3%) and placebo (4.5%) recipients. Dronabinol was found to be safe and effective for anorexia associated with weight loss in patients with AIDS.

The reporting of communicable diseases: a controlled study of Neisseria meningitidis and Haemophilus influenzae infections.

Surveillance systems for communicable diseases in the United States are primarily passive. We compared the passive reporting system for invasive disease caused by Neisseria meningitidis and Haemophilus influenzae with a concurrent, active laboratory-based system in the four metropolitan counties of Tennessee. The passive reporting system identified approximately 50% of all cases that were identified by the active system and accurately reflected trends in disease occurrence during the study period. Of all reported cases, physicians contributed fewer than 4%. Nearly 40% of all hospitals in the study area did not participate in the passive system. This lack of participation resulted in disproportionately increased reporting of disease among blacks. Inconsistencies in case definition within the state also contributed substantially to underreporting and lack of demographic representativeness of reported cases. The median reporting interval (the time from the onset of disease to transmission of the case report to the Centers for Disease Control and Prevention) was 24 days (range, 5-157 days). Efforts to improve surveillance of those infections for which isolation of a pathogen is tantamount to a diagnosis should concentrate on laboratory-based reporting and the use of currently available computer telecommunication systems.

Increased incidence of syphilis in Tennessee during the 1980s: challenges for a new decade.

Although recent increases in the incidence of syphilis are well known to public health officials, the general medical community is less well informed regarding the dramatic rise in cases. We present trend data from Nashville and Tennessee over the past decade. These statistics emphasize specific factors, such as drug abuse, that contribute to new difficulties in controlling this sexually transmitted disease.

Homotypic antibody responses to fresh clinical isolates of human immunodeficiency virus.

Human immunodeficiency virus type 1 (HIV-1) exhibits extensive genomic and antigenic diversity, which is thought to contribute to the failure of the host's immune response to control infection and prevent clinical progression. Part of this failure may be due to utilization by the virus of antigenic variation as a means to escape protective immune responses. Antibody-escape variants of HIV-1 were studied here using fresh clinical isolates and autologous plasmas. HIV-1 was isolated from the plasma of seven people who were all seropositive for at least 2 years, and symptomatic sometime during that period. Isolated viruses were confirmed as HIV-1 by the presence of reverse transcriptase activity in infected culture supernatants, and by positive immunofluorescence using human monoclonal antibody to HIV-1 core protein. Plasma from these people were positive by Western immunoblot (DuPont) for most major HIV-1 (strain IIIB) antigens. These plasmas neutralized three laboratory strains of HIV-1 (i.e., IIIB, RF, and MN) but did not neutralize the homotypic strain in five cases, and had greatly reduced neutralizing titers against the homotypic strain in two cases. Homotypic neutralizing antibodies were absent in autologous plasma obtained 3 months later. When antibody titers were measured by fixed-cell indirect immunofluorescence assays (IFAs), high titers of IgG (1:6400 to 1:25,600) were detected against HIV-1 IIIB, while low titers of only 1:20 to 1:160 were detected against homotypic viral antigens at the time of virus isolation, and remained low 12 and 16 weeks later. No class IgA, IgD, IgE, or IgM antibodies to homotypic viral antigens, as possible IgG-blocking antibodies, were detected by fixed-cell IFAs. Cross-reactions with heterologous donor's plasmas were observed in some cases, and in these cases the cross-reactions were unidirectional. Live-cell IFAs detected IgG in patient's plasma to HIV-1 IIIB-infected cells but not to cells infected with homotypic isolates. These results suggest that it is common for neutralization-resistant HIV-1 variants to appear during the course of infection, and that all or most antigens of these variants are capable of escaping antibody recognition.

Absence of a clinical correlation for complement-mediated, infection-enhancing antibodies in plasma or sera from HIV-1-infected individuals. Multicenter AIDS Cohort Study Group.

Neutralizing and complement-mediated infection-enhancing antibodies to HIV-1 were measured in sera or plasma from 54 HIV-1-positive individuals at various stages of disease, and from an additional 36 HIV-1-positive individuals for whom no clinical data were available. Antibodies were measured in microtiter infection assays utilizing MT-2 cells and the IIIB strain of HIV-1. The frequency of detection of both types of antibodies was identical, being 77 out of 90 cases (86%). Neutralizing and infection-enhancing antibodies were not always found together, and in four cases both were undetectable. No correlation was found between titers of either type of antibody and stage of disease. Furthermore, titers of infection-enhancing antibodies at early stages of disease did not predict rate of disease progression.

Septic shock and acute respiratory distress syndrome after salpingitis caused by Streptococcus pyogenes group A.

A 32-year-old woman with acute salpingitis had signs and symptoms of sepsis, with hypotension, renal failure, acute respiratory distress syndrome, and disseminated intravascular coagulation. Streptococcus pyogenes group A was grown from blood cultures taken at the onset of illness, and salpingitis was confirmed at laparotomy. The patient recovered after appropriate antimicrobial and intensive supportive therapy.