Defining the optimal dose of rifapentine for pulmonary tuberculosis: Exposure-response relations from two phase II clinical trials.

Rifapentine is a highly active antituberculosis antibiotic with treatment-shortening potential; however, exposure-response relations and the dose needed for maximal bactericidal activity have not been established. We used pharmacokinetic/pharmacodynamic data from 657 adults with pulmonary tuberculosis participating in treatment trials to compare rifapentine (n = 405) with rifampin (n = 252) as part of intensive-phase therapy. Population pharmacokinetic/pharmacodynamic analyses were performed with nonlinear mixed-effects modeling. Time to stable culture conversion of sputum to negative was determined in cultures obtained over 4 months of therapy. Rifapentine exposures were lower in participants who were coinfected with human immunodeficiency virus, black, male, or fasting when taking drug. Rifapentine exposure, large lung cavity size, and geographic region were independently associated with time to culture conversion in liquid media. Maximal treatment efficacy is likely achieved with rifapentine at 1,200 mg daily. Patients with large lung cavities appear less responsive to treatment, even at high rifapentine doses.

Serum biomarkers of treatment response within a randomized clinical trial for pulmonary tuberculosis.

RATIONALE: Biomarkers for monitoring response to anti-tuberculosis treatment are needed. We explored immune markers previously published as having predictive capability for 8 week culture status in 39 adults enrolled in a clinical trial in Kampala, Uganda. METHODS: We consecutively selected 20 HIV-negative pulmonary TB subjects with positive cultures, and 19 subjects with negative cultures at the end of intensive phase therapy. At baseline and after 8 weeks, serum was assayed for nine cytokines and soluble cytokine receptors using multiplexed platforms or ELISA. We evaluated their association with week 8 culture status first using single-variable logistic models, then using cross-validated estimates of the C-statistic, a measure of discrimination, of candidate models including 2 or 3 analytes in addition to age. RESULTS: All but one analyte decreased from baseline to week 8 (all p < 0.01). Individual biomarkers were not associated with 8 week culture status. Logistic models including increasing age, higher baseline soluble tumor necrosis factor receptor alpha 1 (sTNF-R1), and higher week 8 C-reactive protein (CRP) concentration classified subjects by culture status with up to 85% accuracy and acceptable discrimination (cross-validated C-statistic 0.76) and calibration (Hosmer-Lemeshow P > 0.2). CONCLUSION: Exploratory post-hoc models including sTNF-R1, CRP, and age, classified 8 week culture status with promising accuracy.

Development and application of a quantitative, specific assay for Cryptosporidium parvum oocyst detection in high-turbidity environmental water samples.

Chlorine-resistant Cryptosporidium parvum oocysts in drinking water play an important role in the epidemiology of cryptosporidiosis. Current methods of detecting these organisms in water are insensitive, labor-intensive, highly subjective, and severely limited by sample turbidity. We describe here an alternative technique utilizing electrochemiluminescence (ECL) technology for detecting C. parvum oocysts in environmental water samples. This method is quantitative, reproducible, and requires only minimal sample processing. Currently, the ECL assay can detect as few as one oocyst in one milliliter of concentrated test sample with sample turbidity of up to 10,000 nephelometric turbidity units. Water and sewer samples collected during a cryptosporidiosis outbreak were tested by ECL assay. Cryptosporidium parvum oocysts were found in the source water at the time of outbreak, and a sharply decreasing level of oocysts in sewer samples was observed over a three-month period following the outbreak.

Lice, nits, and school policy.

BACKGROUND: The epidemiology of head lice infestation is poorly understood. Many schools treat all children with nits as though they are contagious. Children with nits but no lice are often removed from school until they are treated and all visible nits are removed. OBJECTIVE: To investigate the probability that children with nits alone will become infested with lice. DESIGNS: Prospective cohort study. SETTING: Two metropolitan Atlanta elementary schools. PARTICIPANTS: A total of 1729 children were screened for head lice. Twenty-eight children (1.6%) had lice, whereas 63 (3.6%) had nits without lice. Fifty of the 63 children (79%) with nits alone completed follow-up. OUTCOME MEASURE: Conversion (ie, becoming infested with lice) within 14 days after initial screening. RESULTS: Nine of 50 children (18.0%) followed for nits alone converted. Although children who converted did not have significantly more nits than did nonconverters, having nits near the scalp was a risk factor for conversion. Seven of 22 children (31.8%) with >/=5 nits within one fourth inch of the scalp converted, compared with 2 of 28 children (7.1%) with fewer (relative risk: 4.45; 95% confidence interval: 1.03-19.35). This risk remained statistically significant after separately stratifying for sex, recent treatment, and total number of nits. CONCLUSIONS: Although having >/=5 nits within one fourth inch of the scalp was a risk factor for conversion, most children with nits alone did not become infested. Policies requiring exclusion from school and treatment for all children with nits alone are likely excessive. Instead, these children may benefit from repeated examination to exclude the presence of crawling lice.lice, pediculus, lice infestations, pediatrics, school.

Rehabilitating public health infrastructure in the post-conflict setting: epidemic prevention and preparedness in Kosovo.

The war in Kosovo in 1999 resulted in the displacement of up to 1.5 million persons from their homes. On the subsequent return of the refugees and internally displaced persons, one of the major challenges facing the local population and the international community, was the rehabilitation of Kosovo's public health infrastructure, which had sustained enormous damage as a result of the fighting. Of particular importance was the need to develop a system of epidemic prevention and preparedness. But no single agency had the resources or capacity to implement such a program. Therefore, a unique six-point model was developed as a collaboration between the Kosovo Institute of Public Health, the World Health Organization, and an international, non-governmental organization. Important components of the program included a major Kosovo-wide baseline health survey, the development of a province-wide public health surveillance system, rehabilitation of microbiology laboratories, and the development of a local capacity for epidemic response. While all program objectives were met, important lessons were learned concerning the planning, design, and implementation of such a project. This program represents a model that potentially could be replicated in other post-conflict or development settings.

Clinician judgement as a tool for targeting HIV counseling and testing in North Carolina state mental hospitals, 1994.

HIV infection increasingly affects populations that may not appear at high risk based on the use of some traditional targeting strategies. To shed some light on how to more sensitively/effectively identify people who need routine HIV testing and counseling, the objective of this study is to determine the prevalence of HIV infection in North Carolina state mental hospitals and to evaluate clinician judgment as a tool for targeting HIV counseling and testing. The design used is a blinded seroprevalence study. The study population includes all patients admitted to North Carolina state mental hospitals between March 1st and May 31st, 1994. The main outcome measures are the HIV seroprevalence, demographic and diagnostic features, and clinician assessment of the likelihood of HIV infection. The results of the study find that of 2159 study subjects, 35 persons (1.6%) were infected with HIV; of these, 14 (40%) were not previously known to be infected. All 35 HIV infections occurred in persons aged 13-59 years. Within this age group, infection rates were significantly higher for Blacks, males, persons who had a diagnosis of organic brain disease, and persons who had multiple psychiatric diagnoses. However, testing strategies that targeted any of the higher risk groups were insensitive. The rate of HIV infection for persons judged by the admitting clinician to have a high or intermediate likelihood of HIV infection was 26.4 times higher than the rate for those judged to have a low likelihood of infection (2.1 vs. 0.1%, 95% confidence intervals: 3.5-201.3). Of the 14 previously undiagnosed HIV-infected persons, 13 were judged by clinicians to have a high or intermediate likelihood of HIV infection. Moreover, 1258 persons were correctly assessed to have a low likelihood of infection. Conclusions from this study are that an HIV counseling and testing strategy targeting persons (in this setting aged 13-59 years) who were judged by clinicians to have a high or intermediate likelihood of infection, would have identified more than 90% of previously undetected infections while substantially reducing the number of negative HIV tests performed.

A foodborne outbreak of cyclosporiasis caused by imported raspberries.

BACKGROUND: Cyclospora cayetanensis is a recently recognized parasite that causes prolonged diarrheal illness. Its modes of transmission have not been fully determined, although some investigations before 1996 implicated water. Outbreaks of cyclosporiasis in the United States in 1996 and 1997 are evidence of the increasing incidence of this disease. This report describes an outbreak of cyclosporiasis in persons who attended a luncheon on May 23, 1996, near Charleston, South Carolina. METHODS: In this retrospective cohort study, we interviewed all 64 luncheon attendees and the chef regarding food and beverage exposures. A case of cyclosporiasis was defined as diarrhea (> or = 3 loose stools per day or > or = 2 loose stools per day if using antimotility drugs) after attending the luncheon. We identified sporadic cases of cyclosporiasis and traced the implicated food. RESULTS: Of 64 luncheon attendees, 38 (59%) met the case definition. Persons who ate raspberries (relative risk [RR] = 5.4; 95% confidence interval [CI], 2.2-13.2) or potato salad (RR = 1.8; 95% CI, 1.2-2.6) were at significantly increased risk for illness. The population attributable risk percentages were 73% for raspberries and 20% for potato salad. Cyclospora oocysts were found in stools from 11 (85%) of the 13 case patients submitting specimens for testing. Implicated raspberries originated in Guatemala. CONCLUSIONS: Our investigation is one of the first studies to implicate a specific food (raspberries) as a vehicle for transmission of Cyclospora. Because of the apparent increasing incidence of cyclosporiasis in the United States, family physicians should consider testing for Cyclospora in any patient with prolonged, unexplained diarrhea.

Hepatitis A infections in Wisconsin: trends in incidence and factors affecting surveillance, 1986-1995.

From January 1986 through December 1995, 4,143 cases of hepatitis A virus (HAV) infection were reported in Wisconsin. The annual hepatitis A incidence remained stable from 1986 through 1988, with a mean annual rate of 4.7 cases per 100,000 (endemic HAV incidence rate). During 1989-1993, the incidence of HAV infection increased with a peak in 1992 of 19 cases per 100,000 population. A large foodborne outbreak (1992) and community wide outbreaks among African American residents (1989-1993) and Native Americans residents (1991) were associated with these high rates of HAV infection. The community wide outbreaks affected different groups: among African Americans, incidence rates were highest in young adults 15-34 years old; among Native Americans rates were highest in children 5-14 years old. Approximately 2,343 (57%) patients had no apparent risk factor (e.g., international travel, contact with person with HAV infection) for acquiring HAV infection. Factors limiting control of HAV infection in Wisconsin included poor reporting by laboratories (only 19% of all reported cases were independently reported to the Wisconsin Division of Health by a laboratory and fewer than 50% of these reports were from private laboratories), incomplete reporting by Wisconsin physicians or designees (74% of cases confirmed in Wisconsin laboratories were reported in 1995), failure to submit follow-up case report forms (14% of cases), and a prolonged interval between diagnosis and follow-up (> or = 15 days for 610 cases). Efforts should be enhanced to improve the reporting of cases of HAV infection by private laboratories, particularly through the use of automated electronic reporting.

Incomplete sanitation of a meat grinder and ingestion of raw ground beef: contributing factors to a large outbreak of Salmonella typhimurium infection.

Consumers in the United States continue to eat raw or undercooked foods of animal origin despite public health warnings following several well-publicized outbreaks. We investigated an outbreak of Salmonella serotype Typhimurium infection in 158 patients in Wisconsin during the 1994 Christmas holiday period. To determine the vehicle and source of the outbreak, we conducted cohort and case-control studies, and environmental investigations in butcher shop A. Eating raw ground beef purchased from butcher shop A was the only item significantly associated with illness [cohort study: relative risk = 5.8, 95% confidence interval (CI) = 1.5-21.8; case control study: odds ratio = 46.2, 95% CI = 3.8-2751]. Inadequate cleaning and sanitization of the meat grinder in butcher shop A likely resulted in sustained contamination of ground beef during an 8-day interval. Consumer education, coupled with hazard reduction efforts at multiple stages in the food processing chain, will continue to play an important role in the control of foodborne illness.

Golf cart related injuries in a North Carolina island community, 1992-4.

OBJECTIVES AND METHODS: The use of electric golf carts for roadway transportation is increasing in many regions of the United States, but injuries associated with the operation of these vehicles have not been previously described. In response to reports of golf cart related injuries in a North Carolina island community, we reviewed ambulance call report (ACR) information to identify and describe all injuries related to golf cart operation in this community in 1992-4. We also conducted telephone interviews with the subset of injured people who consented to be contacted. SETTING: Bald Head Island, North Carolina. RESULTS: Twenty two people were included in the case series, and 55% of these provided interview information to supplement ACR data. Fifty nine per cent of the 22 injured people were injured when they fell from a moving golf cart; of those injured in this manner, all with available information on seating position were passengers (rather than drivers). Eighty six per cent received immediate medical treatment at a mainland hospital. Thirty two per cent of injury incidents occurred among children aged 10 or younger. Forty per cent of injured adults were known to have been drinking alcohol before their injuries occurred, while alcohol was not known to have been involved in any of the children's injuries (in terms of drinking either by children or by accompanying adults). CONCLUSIONS: In settings where golf carts are used for road transportation, their users and traffic safety officials should be aware of potential safety hazards associated with the use of these vehicles, and installation of appropriate occupant restraints should be considered seriously.

Body mass and breast cancer. Relationship between method of detection and stage of disease.

BACKGROUND: Obesity is associated with advanced stage breast cancer at diagnosis and a poorer prognosis. Stage of breast cancer at diagnosis is also strongly influenced by the method of cancer detection. The objective of this study was to determine the relationship between body mass index (BMI) and breast cancer disease stage, taking into account the method of cancer detection (i.e., self-detection, screening mammography, and clinical breast examination [CBE]). METHODS: From 1988 to 1990, 2863 patients with invasive breast cancer were identified through a statewide, population-based, cancer reporting system and were interviewed as part of a larger study of breast cancer etiology. Stage of disease was classified as either localized or nonlocalized (regional and distant disease combined). The relation between BMI and disease stage was examined by using multiple logistic regression adjusting for age, education, race, year of diagnosis, and prior mammography use. RESULTS: Thirty-eight percent (1092 of 2863) of the women had nonlocalized breast cancer. A strong dose-response relationship was observed between increased BMI and the likelihood of nonlocalized disease (P < 0.001). However, this association was present only among the 55% of women (1585 of 2863) who self-detected their tumors. The odds ratios for nonlocalized cancer increased from 1.0 for the lowest quintile of BMI to 1.3, 1.6, 1.7, and 1.8 for the second through fifth quintiles, respectively, for this group. CONCLUSIONS: Greater body mass was associated with nonlocalized breast cancer; however, this association was restricted to women who detected their own cancer. No association was found between BMI and stage of disease among cases detected by either mammography or CBE.

An outbreak of cryptosporidiosis associated with a resort swimming pool.

An outbreak of cyptosporidiosis occurred in late April 1993 among resort hotel guests which was temporally associated with, but geographically distant from, a massive waterborne outbreak of cryptosporidiosis in Milwaukee, Wisconsin, that occurred in late March and early April of 1993. A case-control study was performed among groups with members who reported illness and among a systemic sample of groups who stayed at the resort hotel during the risk period. Of 120 persons interviewed, 51 (43%) met the case definition. Swimming in the resort hotel's pool was significantly associated with case status (OR = 9.8; 95% Cl 3.4, 29.7), as was consumption of ice from the hotel's ice machines (OR = 2.3; 95% Cl 1.01, 5.2). When analysis was restricted only to laboratory-confirmed cases and controls, swimming pool use was the only risk factor significantly associated with illness (OR = 13.0; 95% Cl 2.6, 88.7). Following waterborne outbreaks of cryptosporidiosis associated with water supplies, swimming pools should be considered as possible ongoing sources for transmission regionally.

Massive outbreak of waterborne cryptosporidium infection in Milwaukee, Wisconsin: recurrence of illness and risk of secondary transmission.

Contamination of the public water supply in Milwaukee during March and April 1993 resulted in a massive outbreak of cryptosporidium infection. We investigated the clinical and epidemiological features of visitors to the Milwaukee area in whom cryptosporidiosis developed, and we conducted a telephone survey of Milwaukee County households to evaluate the risk of recurrent illness and secondary transmission. Cryptosporidium infection during this outbreak generally seemed more severe than cases described in previous reports of large case series. The risk of secondary transmission within a household was low (5%) when the index case involved an adult. The recurrence of watery diarrhea after apparent recovery was a frequent occurrence among visitors with laboratory-confirmed cryptosporidium infection (39%) and among visitors and Milwaukee County residents with clinical infection (21%). The interval between the initial recovery and the onset of recurrence was prolonged (> or = 5 days) in 6%-8% of persons. This pattern of recurrence and its impact on transmission and our understanding of the pathophysiological mechanisms of cryptosporidium infection merit further investigation.