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Background: Patients infected with HIV who experience increases in CD4(+) cell counts are at reduced risk for opportunistic infections. However, the safety of discontinuing prophylaxis against Mycobacterium avium complex has been uncertain.Objective: To compare the rate of M. avium complex infection in patients with increased CD4(+) cell counts who receive azithromycin and those receiving placebo.Design: Randomized, double-blind, placebo-controlled trial.Setting: 29 university-based clinical centers in the United States.Participants: 643 HIV-1-infected patients with a previous CD4(+) cell count less than 0.05 x 10(9) cells/L and a sustained increase to greater than 0.10 x 10(9) cells/L during antiretroviral therapy.Intervention: Azithromycin, 1200 mg once weekly (n = 321), or matching placebo (n = 322).Measurements: Mycobacterium avium complex cultures, CD4(+) cell counts, and clinical evaluations for AIDS-defining illnesses and bacterial infections were done every 8 weeks. Plasma HIV-1 RNA levels were measured at 16-week intervals.Results: During follow-up (median, 16 months), 2 cases of M. avium complex infection were reported among the 321 patients assigned to placebo (incidence rate, 0.5 event per 100 person-years [95% CI, 0.06 to 1.83 events per 100 person-years]) compared with no cases among the 322 patients assigned to azithromycin (CI, 0 to 0.92 events per 100 person-years), resulting in a treatment difference of 0.5 event per 100 person-years (CI, -0.20 to 1.21 events per 100 person-years) for placebo versus azithromycin. Both cases were atypical in that M. avium complex was localized to the vertebral spine. Patients receiving azithromycin were more likely than those receiving placebo to discontinue treatment with the study drug permanently because of adverse events (8% vs. 2%; hazard ratio, 0.24 [CI, 0.10 to 0.57]).Conclusions: Prophylaxis against Mycobacterium avium complex can safely be withdrawn or withheld in adults with HIV infection who experience increases in CD4(+) cell count while receiving antiretroviral therapy. [ABSTRACT FROM AUTHOR]

Investigates the safety of stopping antibiotic treatments that prevent Mycobacterium avium complex (MAC) infections in persons whose CD4[sup+] cell counts have exceeded 100 cells/mm[sup3]. Focus on HIV infected persons with cell count below 50 cells/mm[sup3]; Comparison of reactions between placebo and anti-MAC antibiotic fed patients; Possibility that the results could be misleading.

Purpose: To describe a nosocomial outbreak of Legionella micdadei pneumonia in transplant patients and to characterize the source of the outbreak and the control measures utilized.Subjects and Methods: We performed retrospective Legionella micdadei serologic testing to enhance case finding in transplant patients with pneumonia that lacked a documented microbial etiology, as well as prospective environmental surveillance of water sites and testing for Legionella in clinical specimens.Results: During a 3-month period, 12 cases of Legionella micdadei pneumonia were identified either by culture or serologic testing among 38 renal and cardiac transplant patients. Legionella micdadei isolates from hot water sources were found by pulsed-field gel electrophoresis to have a DNA banding pattern that was identical to the isolates from the first 3 culture-positive cases and from 2 cases that occurred 16 months later.Conclusions: Hospitals caring for organ transplant recipients and other immunosuppressed patients must be aware of the possibility of environmental sources of outbreaks of Legionella infection. A first-line screen with the Legionella urine antigen test will identify Legionella pneumophila serogroup 1. However, specific cultures in outbreak situations should be considered to identify other Legionella pneumophila serotypes and the nonpneumophila Legionella species. [ABSTRACT FROM AUTHOR]

Background: To facilitate mass distribution of azithromycin, trachoma control programmes use height instead of weight to determine dose for children 6 months to 15 years old. WHO has recommended azithromycin distribution to children 1-11 months old to reduce mortality in high mortality settings under carefully monitored conditions. Weight was used to determine dose in children 1-5 months old in studies of azithromycin distribution for child survival, but a simplified approach using age or height for all aged 1-11 months old could increase programme efficiency in real-world settings., Methods: This secondary analysis used data from two cluster randomised trials of azithromycin distribution for child mortality in Niger and Burkina Faso. An exhaustive search algorithm was developed to determine the optimal dose for different age groups, using tolerance limits of 10-20 mg/kg for children 1-2 months old and 15-30 mg/kg for children 3-11 months old. Height-based dosing was evaluated against the existing trachoma dosing pole and with a similar exhaustive search., Results: The optimal two-tiered age-based approach suggested a dose of 80 mg (2 mL) for children 1-2 months old and 160 mg (4 mL) for children 3-11 months old. Under this schedule, 89%-93% of children would have received doses within tolerance limits in both study populations. Accuracy was 93%-94% with a three-tiered approach, which resulted in doses of 80 mg (2 mL), 120 mg (3 mL) and 160 mg (4 mL) for children 1-2, 3-4 and 5-11 months old, respectively. For children 1-5 months old, the existing height pole would result in 70% of doses within tolerance limits. The optimisation identified height-based dosing options with 95% accuracy, although this would require changes to the existing dosing pole as well as additional training to measure infants lying flat., Conclusions: Overall, an age-based approach with two age tiers resulted in high accuracy while considering both concerns about overdosing in this young population and simplicity of field operations., Competing Interests: Competing interests: CK is affiliated with Pfizer, which supplied the azithromycin and placebo used in the trials that generated the data analysed in this manuscript., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: Two phase 1/phase 2 studies assessed 2 formulations of investigational bivalent Clostridioides (Clostridium) difficile vaccine (QS-21 adjuvanted toxoid and toxoid-alone) in healthy adults 50-85 years of age., Methods: The QS-21 adjuvanted toxoid vaccine study randomized subjects 3:1 to 100 μg QS-21-containing C difficile vaccine or placebo administered in a shortened-month (Months 0, 1, 3) or day (Days 1, 8, 30) regimen. The toxoid-alone vaccine study randomized subjects 3:3:1 to receive 100 or 200 μg unadjuvanted C difficile vaccine formulation or placebo in Stages 1 and 2 (sentinel cohorts of different age groups), and 3:1 to receive the selected dose of unadjuvanted C difficile vaccine formulation or placebo in Stage 3 (Days 1, 8, 30). Safety was the primary outcome for both studies. Immunogenicity was determined by measuring serum toxin A- and B-specific neutralizing antibodies., Results: In the day regimen, 10 reports across both studies of grade 3 injection site redness postdose 2 triggered predefined stopping rules. Local reactions in both studies were more common among vaccine versus placebo recipients. Injection site pain predominated and was generally mild in severity. Systemic events were infrequent and generally mild-to-moderate in severity. Adverse events were reported by 50.0%-75.0% and 16.7%-50.0% of subjects in the QS-21 and toxoid-alone studies, respectively. Immune responses peaked around Day 37 (shortened-month regimen) or between Day 15 and Month 2 (day regimen) and remained above baseline throughout follow-up., Conclusions: Both formulations demonstrated robust immunogenicity. Both studies stopped early due to grade 3 injection site redness postdose 2 of the day regimen; neither formulation progressed to later stage development. Instead, an aluminum hydroxide-containing formulation of the vaccine candidate administered at 0, 1, and 6 months, which was safe and immunogenic in phase 1 and 2 studies, advanced to phase 3 studies., Competing Interests: Conflicts of Interest All authors are employees of Pfizer Inc and may hold stock or stock options., (Copyright © 2021 Pfizer Inc. Published by Elsevier Ltd.. All rights reserved.)

Background: Clostridium difficile causes toxin-mediated nosocomial diarrhea and community-acquired infections; no preventive vaccine is licensed. In this phase 2 study, we explored safety, tolerability, and immunogenicity in older US adults of an investigational bivalent C. difficile vaccine that contains equal dosages of genetically and chemically detoxified toxins A and B., Methods: Conducted from July 2015 through March 2017, 855 healthy adults aged 65-85 years from 15 US centers were randomized 3:3:1 to receive vaccine (100 or 200 μg) or placebo at 0, 1, and 6 months (month regimen) or 1, 8, and 30 days (day regimen). Serum toxin A- and B-specific neutralizing antibodies were measured. Participant-reported local reactions (LRs) and systemic events (SEs), adverse events (AEs), serious AEs, newly diagnosed chronic medical conditions, and immediate AEs were recorded., Results: The 200-μg dose level elicited higher immune responses than the 100-µg dose level across regimens. Compared with the day regimen, the month regimen induced stronger and more persistent immune responses that remained elevated 12 months after dose 3. Responses peaked at month 7 (month regimen) and day 37 (day regimen). LRs (primarily injection site pain) were more frequent in vaccine recipients than controls; SE frequency was similar across groups. More related AEs were reported in the day regimen group than the month regimen group., Conclusions: The C. difficile vaccine was safe, well tolerated, and immunogenic in healthy US adults aged 65-85 years. Immune responses were particularly robust in the 200-μg month regimen group. These results support continued vaccine development., Clinical Trials Registration: NCT02561195., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Clostridium difficile infection (CDI) is a major global cause of nosocomial and community-acquired infections. Despite potentially severe or fatal complications and frequent recurrence, no preventive vaccine is currently available. This randomized, observer-blinded, placebo-controlled phase 1 study in older Japanese adults evaluated safety and immunogenicity of an investigational C difficile vaccine containing a mixture of genetically detoxified and chemically inactivated toxoids, A and B., Methods: Healthy Japanese adults aged 65 to 85 years were randomized in a 3:3:2 ratio to receive 100 or 200 μg of C difficile vaccine or placebo, respectively, at 0, 1, and 6 months (month regimen) or 1, 8, and 30 days (day regimen). The primary objective was safety evaluation. Vaccine immunogenicity, the secondary objective, was determined by assessing toxin A- and toxin B-specific neutralizing antibody levels in human sera., Results: Local reactions were reported by up to 33.3% of subjects per dose in the month regimen; percentages were generally higher in the 200-μg group. Such reactions were all mild or moderate in severity and generally transient. No adverse events in the month regimen led to subject withdrawal, and no serious adverse events were considered vaccine related. Further enrollment and dosing in the day regimen were discontinued after 3 subjects in the 100-μg group reported severe redness after dose 2. In the month regimen study arm, immune responses as measured by toxin-neutralizing antibody geometric mean concentrations, geometric mean fold rises, and proportions of subjects achieving prespecified fold rises were generally higher in the 200-μg group, peaked at month 7, and remained elevated at month 12., Conclusions: The C difficile vaccine candidate was safe, well tolerated, and immunogenic when administered to healthy older Japanese adults at 0, 1, and 6 months. Results support continued development of the vaccine for the prevention of CDI. ClinicalTrials.gov identifier: NCT02725437., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Antimicrobial resistance (AMR) and the associated morbidity and mortality due to bacterial pathogens have been increasing globally to alarming levels. The World Health Organization (WHO) has called for global action on AMR, supported worldwide by governments, health ministries and health agencies. Many potential solutions to stem AMR are being discussed and implemented. These include increases in antimicrobial stewardship, investment in research and development to design new classes of antibiotics, and reduction of antibiotic use in rearing of livestock. However, vaccines as tools to reduce AMR have historically been under-recognized in these discussions, even though their effectiveness in reducing disease and AMR is well documented. This review article seeks to highlight the value of vaccines as an additional modality to combat AMR globally, using select examples. It also will provide perspectives on how vaccines could be more effectively used in this effort.

Background: A data monitoring committee (DMC) has special responsibilities for protecting the safety of clinical trial participants. Few guidance documents are available that address the operations and mechanics of establishing, serving on, or reporting to a DMC. This article provides a practical guide to sponsors, institutions, and individuals responsible for, or serving on, a DMC., Methods: A workgroup of professionals from academia and not-for-profit and commercial organizations that included investigators, statisticians, patient advocates, and ethicists met to define the essential elements of planning, coordinating, and populating a DMC. All members of the group have formed, served on, advised, or worked with DMCs., Results: The group outlined the objectives and mechanics of running a DMC, including operational and practical considerations, membership characteristics, roles, members' liability, and indemnification. Further, it delineated the roles and responsibilities of each DMC member., Conclusions: The group recommended practices for each phase of the DMC process from inception through execution of a clinical trial, with appropriate considerations for confidentiality. The group's practical guidance should assist in comprehensive oversight of appropriate clinical trials and should help DMC members execute their obligations with greater assurance.

Background: The etiology of hospital-acquired or ventilator-associated bacterial pneumonia (HABP/VABP) is often multidrug-resistant infections. The evaluation of new antibacterial drugs for efficacy in this population is important, as many antibacterial drugs have demonstrated limitations when studied in this population. HABP/VABP trials are expensive and challenging to conduct due to protocol complexity and low patient enrollment, among other factors. The Clinical Trials Transformation Initiative (CTTI) seeks to advance antibacterial drug development by streamlining HABP/VABP clinical trials to improve efficiency and feasibility while maintaining ethical rigor, patient safety, information value, and scientific validity., Methods: In 2013, CTTI engaged a multidisciplinary group of experts to discuss challenges impeding the conduct of HABP/VABP trials. Separate workstreams identified challenges associated with HABP/VABP protocol complexity. The Project Team developed potential solutions to streamline HABP/VABP trials using a Quality by Design approach., Results: CTTI recommendations focus on 4 key areas to improve HABP/VABP trials: informed consent processes/practices, protocol design, choice of an institutional review board (IRB), and trial outcomes. Informed consent processes should include legally authorized representatives. Protocol design decisions should focus on eligibility criteria, prestudy antibacterial therapy considerations, use of new diagnostics, and sample size. CTTI recommends that sponsors use a central IRB and discuss trial endpoints with regulators, including defining a clinical failure and evaluating the impact of concomitant antibacterial drugs., Conclusions: Streamlining HABP/VABP trials by addressing key protocol elements can improve trial startup and patient recruitment/retention, reduce trial complexity and costs, and ensure patient safety while advancing antibacterial drug development., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Assays to identify infectious organisms are critical for diagnosis and enabling the development of therapeutic agents. The demonstration that individuals with a 32-bp deletion within the CCR5 locus were resistant to human immunodeficiency virus (HIV) infection, while those heterozygous for the mutation progressed more slowly, led to the discovery of maraviroc (MVC), a CCR5 antagonist. As MVC is only active against CCR5-tropic strains of HIV, it was critical to develop a diagnostic assay to identify appropriate patients. Trofile™, a novel phenotypic tropism assay, was used to identify patients with CCR5-tropic virus for the MVC development program. Results of these clinical studies demonstrated that the assay correctly identified patients likely to respond to MVC. Over time, the performance characteristics of the phenotypic assay were enhanced, necessitating retesting of study samples. Genotypic tropism tests that have the potential to allow for local use and more rapid turnaround times are also being developed., (© 2015 New York Academy of Sciences.)

The enormous gains made in public health during the 20th century, through the prevention and treatment of infectious disease, have contributed to dramatic improvements in the quality and length of the human lifespan. Continued advances in medicine are dependent on addressing several challenges including the increase in existing and new resistance to antibiotics, the decrease in productivity of the research and development (R&D) ecosystem, uncertain regulatory pathways, and an economic environment that rewards innovation for developing therapeutics that involve long cycle times from idea to a product. In this article, we consider important issues pertaining to the development of vaccines with particular emphasis on preclinical requirements, optimal dose selection, design, execution, and reporting of clinical trials for regulatory submission, planning and implementation of post-approval life-cycle programs, and emerging themes in therapeutic vaccines., (© 2015, The American College of Clinical Pharmacology.)

To bring new antibacterial drugs to the market is challenging because discovery of new agents is difficult, two large trials per indication are needed in accordance with traditional regulatory requirements, and the economic reward is limited if the use of new antibiotics is constrained. These challenges have resulted in an alarmingly thin antibiotic pipeline, despite the rapid and continued growth in the need for new drugs. Approaches that balance the quantity of data needed for registration with the unmet medical need would encourage work in this area. Therefore, a tiered regulatory framework that allows either disease-based or pathogen-based label indications is proposed, with label wording that promotes the most appropriate use of new agents. Such a framework is within the bounds of present regulatory approaches, is amenable to international harmonisation, and would be a welcome step towards the facilitation of a robust and sustainable discovery and development infrastructure., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Large-scale electronic health record research introduces biases compared to traditional manually curated retrospective research. We used data from a community-acquired pneumonia study for which we had a gold standard to illustrate such biases. The challenges include data inaccuracy, incompleteness, and complexity, and they can produce in distorted results. We found that a naïve approach approximated the gold standard, but errors on a minority of cases shifted mortality substantially. Manual review revealed errors in both selecting and characterizing the cohort, and narrowing the cohort improved the result. Nevertheless, a significantly narrowed cohort might contain its own biases that would be difficult to estimate.

Background: Catheter-related bloodstream infection (CRBSI) causes substantial morbidity and mortality, but few randomized, controlled studies have been conducted to guide therapeutic interventions., Methods: To determine whether linezolid would be noninferior to vancomycin in patients with CRBSI, we conducted an open-label, multicenter, comparative study. Patients with suspected CRBSI were randomized to receive linezolid or vancomycin (control group). The primary end point was microbiologic outcome at test of cure 1-2 weeks after treatment, as assessed by step-down procedure. The first analysis population was complicated skin and skin structure infection (cSSSI) in patients with suspected CRBSI; patients with CRBSI were analyzed if noninferiority criteria (lower bound of the 95% confidence interval [CI] not outside -15%) were met., Results: Noninferiority criteria were met for cSSSI (microbiologic success rate for linezolid recipients, 89.6% [146 for 163 patients]; for the control group, 89.9% [134 of 149]; 95% CI, -7.1 to 6.4) and CRBSI (for linezolid recipients, 86.3% [82 of 95]; for the control group, 90.5% [67 of 74]; 95% CI, -13.8 to 5.4). The frequency and severity of adverse events were similar between groups. Mortality rates were 10.4% for linezolid recipients (28 of 269 patients) and 10.1% for control subjects (26 of 257) in the modified intent-to-treat population (i.e., all patients with gram-positive baseline culture) through test of cure, and they were 21.5% for linezolid recipients (78 of 363) and 16.0% for the control group (58 of 363; 95% CI, -0.2 to 11.2) for all treated patients through poststudy treatment day 84., Conclusions: Linezolid demonstrated microbiologic success rates noninferior to those for vancomycin in patients with cSSSIs and CRBSIs caused by gram-positive organisms. Patients with catheter-related infections must be carefully investigated for the heterogeneous underlying causes of high morbidity and mortality, particularly for infections with gram-negative organisms.

Data mining in electronic medical records may facilitate clinical research, but much of the structured data may be miscoded, incomplete, or non-specific. The exploitation of narrative data using natural language processing may help, although nesting, varying granularity, and repetition remain challenges. In a study of community-acquired pneumonia using electronic records, these issues led to poor classification. Limiting queries to accurate, complete records led to vastly reduced, possibly biased samples. We exploited knowledge latent in the electronic records to improve classification. A similarity metric was used to cluster cases. We defined discordance as the degree to which cases within a cluster give different answers for some query that addresses a classification task of interest. Cases with higher discordance are more likely to be incorrectly classified, and can be reviewed manually to adjust the classification, improve the query, or estimate the likely accuracy of the query. In a study of pneumonia--in which the ICD9-CM coding was found to be very poor--the discordance measure was statistically significantly correlated with classification correctness (.45; 95% CI .15-.62).

Azithromycin when used in combination with faster-acting antimalarials has proven efficacious in treating Plasmodium falciparum malaria in phase 2 clinical trials. The aim of this study was to establish optimal combination ratios for azithromycin in combination with either dihydroartemisinin or quinine, to determine the clinical correlates of in vitro drug sensitivity for these compounds, and to assess the cross-sensitivity patterns. Seventy-three fresh P. falciparum isolates originating from patients from the western border regions of Thailand were successfully tested for their drug susceptibility in a histidine-rich protein 2 (HRP2) assay. With overall mean fractional inhibitory concentrations of 0.84 (95% confidence interval [CI]=0.77 to 1.08) and 0.78 (95% CI=0.72 to 0.98), the interactions between azithromycin and dihydroartemisinin, as well as quinine, were classified as additive, with a tendency toward synergism. The strongest tendency toward synergy was seen with a combination ratio of 1:547 for the combination with dihydroartemisinin and 1:44 with quinine. The geometric mean 50% inhibitory concentration (IC50) of azithromycin was 2,570.3 (95% CI=2,175.58 to 3,036.58) ng/ml. The IC50s for mefloquine, quinine, and chloroquine were 11.42, 64.4, and 54.4 ng/ml, respectively, suggesting a relatively high level of background resistance in this patient population. Distinct correlations (R=0.53; P=0.001) between quinine in vitro results and parasite clearance may indicate a compromised sensitivity to this drug. The correlation with dihydroartemisinin data was weaker (R=0.34; P=0.038), and no such correlation was observed for azithromycin. Our in vitro data confirm that azithromycin in combination with artemisinin derivatives or quinine exerts additive to synergistic interactions, shows no cross-sensitivity with traditional antimalarials, and has substantial antimalarial activity on its own.

Realistically, global elimination of trachoma could not have been considered until the maturation of innovation and public will that converged with the formation of both the Alliance for the Global Elimination of Trachoma by the year 2020 (GET2020) in 1997 and the public-private partnership, the International Trachoma Initiative (ITI) in 1998. Public-private partnerships are cross-sector collaborations that bring heterogeneous capabilities together to work on difficult problems for which the individual partners share common goals. The work of the ITI and partners to date demonstrates that the SAFE strategy reviewed in this article can work, and that it will revolutionize the control of blinding trachoma. Programs working to eliminate trachoma can achieve the GET2020 goals through expanded partnerships, commitment, and research on program integration into evolving health systems.

Azithromycin, the most potent antimalarial macrolide antibiotic, is synergistic with quinine against Plasmodium falciparum in vitro. We assessed combinations of azithromycin and quinine against uncomplicated P. falciparum malaria at the Armed Forces Research Institute of Medical Sciences-Kwai River Clinical Center along the Thailand-Myanmar border, an area with a high prevalence of multidrug-resistant P. falciparum. Four regimens were assessed in an open-label dose-ranging design involving 61 volunteers. All received oral quinine (Q; 30 mg/kg/day divided every 8 hours for 3 days) with oral azithromycin (Az; 500 mg twice a day for 3 days, 500 mg twice a day for 5 days, or 500 mg three times a day for 3 days). A comparator group received quinine and doxycycline (Dx; 100 mg twice a day for 7 days). Study observation was 28 days per protocol. Sixty volunteers completed the study. Seven days of QDx cured 100% of the volunteers. One failure occurred in the lowest QAz regimen (on day 28) and none occurred in either of the two higher Az regimens. Cinchonism occurred in nearly all subjects. Overall, the azithromycin regimens were well tolerated, and no volunteers discontinued therapy. Three- and five-day azithromycin-quinine combination therapy appears safe, well tolerated, and effective in curing drug-resistant P. falciparum malaria. Further evaluation, especially in pediatric and obstetric populations, is warranted.

Skin and soft tissue infections (SSTIs) are a common cause of morbidity in both the community and the hospital. An SSTI is classified as complicated if the infection has spread to the deeper soft tissues, if surgical intervention is necessary, or if the patient has a comorbid condition hindering treatment response (e.g., diabetes mellitus or human immunodeficiency virus). The purpose of this study was to compare linezolid to vancomycin in the treatment of suspected or proven methicillin-resistant gram-positive complicated SSTIs (CSSTIs) requiring hospitalization. This was a randomized, open-label, comparator-controlled, multicenter, multinational study that included patients with suspected or proven methicillin-resistant Staphylococcus aureus (MRSA) infections that involved substantial areas of skin or deeper soft tissues, such as cellulitis, abscesses, infected ulcers, or burns (<10% of total body surface area). Patients were randomized (1:1) to receive linezolid (600 mg) every 12 h either intravenously (i.v.) or orally or vancomycin (1 g) every 12 h i.v. In the intent-to-treat population, 92.2% and 88.5% of patients treated with linezolid and vancomycin, respectively, were clinically cured at the test-of-cure (TOC) visit (P=0.057). Linezolid outcomes (124/140 patients or 88.6%) were superior to vancomycin outcomes (97/145 patients or 66.9%) at the TOC visit for patients with MRSA infections (P<0.001). Drug-related adverse events were reported in similar numbers in both the linezolid and the vancomycin arms of the trial. The results of this study demonstrate that linezolid therapy is well tolerated, equivalent to vancomycin in treating CSSTIs, and superior to vancomycin in the treatment of CSSTIs due to MRSA.

Background: The objective of this study was to characterize the pharmacokinetics and tolerance of a single intravenous (IV) azithromycin dose in children., Methods: Subjects were stratified into 4 age groups: 0.5-2 years; >2-<6 years; 6-<12 years; and 12-<16 years. Each subject received a single 10 mg/kg dose (500 mg maximum) infused in 1 hour. Serial venous blood samples were obtained for a 168-hour period, and laboratory safety evaluations were performed immediately preceding azithromycin administration and at the conclusion of the study. Serum azithromycin concentrations were quantified with a validated high performance liquid chromatography method with mass spectrometric detection. Pharmacokinetic indices were calculated for each subject by noncompartmental techniques., Results: Thirty-two subjects (6.7 +/- 5.0 years, 11 boys) participated. Mean serum concentration-time data were comparable for the 4 age groups. For all subjects with evaluable data, the mean area under the curve from 0 to 72 hours (AUC0-72) was 8.2 microg . h/mL (n = 26), the maximum concentration (Cmax) was 2.4 microg/mL and the elimination half-life (t1/2) was 65.2 hours (n = 25). The AUC0-72 and Cmax were not associated with age. The dose was well-tolerated with no serious adverse events., Conclusion: The disposition of azithromycin after a single 10-mg/kg IV dose (maximum labeled adult dose of 500 mg) is comparable in pediatric patients between 0.5 and 16 years of age. These pharmacokinetic data can be used to guide dose selection for future therapeutic trials of IV azithromycin in pediatric patients.

We studied 149 children and adolescents 3-17 years of age with clinical typhoid fever who were treated with either oral azithromycin (20 mg/kg per day; maximum dose, 1000 mg/day) or intravenous ceftriaxone (75 mg/day; maximum dose, 2.5 g/day) daily for 5 days. Blood and stool specimens were obtained for culture before the initiation of therapy and were repeated on days 4 and 8 of treatment. Isolation of Salmonella enterica serovar Typhi or S. enterica serovar Paratyphi from the initial culture was required for inclusion in the final analysis. S. Typhi was isolated from 68 patients, 32 of whom were receiving azithromycin. Cure was achieved in 30 (94%) of 32 patients in the azithromycin group and in 35 (97%) of 36 patients in the ceftriaxone group (P=NS). Mean time to clearance of bacteremia was longer in the azithromycin group than in the ceftriaxone group. No patient who received azithromycin had a relapse, compared with 6 patients who received ceftriaxone. A 5-day course of azithromycin was found to be an effective treatment for uncomplicated typhoid fever in children and adolescents.

Community distribution of azithromycin has an important role to play in trachoma control. Previous studies have suggested that this may increase the prevalence of macrolide-resistant Streptococcus pneumoniae. S. pneumoniae was isolated from children under 7 years of age in Rombo District, northern Tanzania, before and 2 and 6 months after community-wide administration of azithromycin. Overall carriage rates were 11, 12, and 7%, respectively. Only one macrolide-resistant isolate carrying the mef gene was obtained 6 months after azithromycin administration. This contrasted with cotrimoxazole and penicillin resistance, both of which were common (cotrimoxazole resistance, 42, 43, and 47%, and penicillin resistance, 21, 17, and 16% at baseline, 2 months, and 6 months, respectively). There was a significant association between cotrimoxazole and penicillin resistance (P < 0.0001, Fisher's exact). These data suggest that in communities where macrolide resistance is rare, azithromycin distribution for trachoma control is unlikely to increase the prevalence of resistant organisms.

Initial field malaria prophylaxis trials with azithromycin revealed insufficient efficacy against falciparum malaria to develop azithromycin as a single agent. The objective of this in vitro study was to determine the best drug combination(s) to evaluate for future malaria treatment and prophylaxis field trials. In vitro, azithromycin was tested in combination with chloroquine against 10 representative Plasmodium falciparum isolates. Azithromycin was also assessed in combination with eight additional antimalarial agents against two or three multidrug-resistant P. falciparum isolates. Parasite susceptibility testing was carried out with a modification of the semiautomated microdilution technique. The incubation period was extended from the usual 48 h to 68 h. Fifty percent inhibitory concentrations (IC(50)s) were calculated for each drug alone and for drugs in fixed combinations of their respective IC(50)s (1:1, 3:1, 1:3, 4:1, 1:4, and 5:1). These data were used to calculate fractional inhibitory concentrations and isobolograms. Chloroquine-azithromycin studies revealed a range of activity from additive to synergistic interactions for the eight chloroquine-resistant isolates tested, while an additive response was seen for the two chloroquine-sensitive isolates. Quinine, tafenoquine, and primaquine were additive to synergistic with azithromycin, while dihydroartemisinin was additive with a trend toward antagonism. The remaining interactions appeared to be additive. These results suggest that a chloroquine-azithromycin combination should be evaluated for malaria prophylaxis and that a quinine-azithromycin combination should be evaluated for malaria treatment in areas of drug resistance.

Azithromycin and clarithromycin were paired with other antibiotics to test synergistic activity against 300 multidrug-resistant pathogens isolated from cystic fibrosis (CF) patients. Clarithromycin-tobramycin was most active against Pseudomonas aeruginosa and inhibited 58% of strains. Azithromycin-trimethoprim-sulfamethoxazole, azithromycin-ceftazidime, and azithromycin-doxycycline or azithromycin-trimethoprim-sulfamethoxazole inhibited 40, 20, and 22% of Stenotrophomonas maltophilia, Burkholderia cepacia complex, and Achromobacter (Alcaligenes) xylosoxidans strains, respectively.

There are conflicting reports of an association between Chlamydia pneumoniae (C. pneumoniae) infection and coronary artery disease (CAD); randomized trials of antibiotics for the secondary prevention of CAD are currently underway. Physicians may be tempted to believe that their choice of antibiotic class in treating any infection may alter the risk of CAD. Our objective was to determine if the use of antibiotics with antichlamydial activity in the general population reduces the risk of myocardial infarction. A healthcare claims database with 354,258 patients with continuous health and pharmacy coverage for at least 2 years between January 1, 1991 and December 31, 1997 was used for the analyses. Hazard ratios were derived from proportional hazards models with time-dependent covariates, relating antibiotic prescription to first claim related to incident first myocardial infarction during the observation period, adjusting for previous CAD, age, sex, diabetes, hypertension, hyperlipidemia, and chronic obstructive pulmonary disease. There were a total of 1,684,091 person-years of observation and 16,139 incident myocardial infarctions. The adjusted hazard ratios were 1.10 (95% confidence intervals [CI] 1.04 to 1.16) for macrolides, 1.20 (95% CI 1.13 to 1.26) for quinolones, 1.10 (95% CI 0.96 to 1.21) for cephalosporins, 1.00 (95% CI 0.96 to 1.06) for tetracyclines, 1.01 (95% CI 0.96 to 1.06) for penicillins, and 1.13 (95% CI 0.98 to 1.30) for trimetroprim-sulfamethoxazole. The hazard ratios for individual antibiotics with activity against C. pneumoniae within each group were similar. Use of antibiotics with activity against C. pneumoniae does not reduce the risk of myocardial infarction in the general population.

Purpose: To determine whether treating infections with antibiotics that have antichlamydial activity decreases the risk of ischemic stroke in the elderly., Subjects: We analyzed data from 199 553 subjects 65 years and older in a health care claims database who had continuous health and pharmacy coverage for at least 2 years between January 1, 1991, and September 30, 1997. Using proportional hazards models with time-dependent covariates for prior antibiotic prescription and adjusting for cardiovascular risk factors, we determined the associations between antibiotic use and first claim for ischemic stroke (n = 7,335) during the observation period., Results: Rates of stroke (per 1,000 person-years) were 6.64 for macrolides, 9.27 for quinolones, 7.49 for tetracyclines, 6.88 for penicillins, 7.97 for cephalosporins, 8.58 for trimethoprim-sulfamethoxazole, and 7.29 for subjects with no antibiotic claims. The adjusted hazard ratios (HR) were 0.94 (95% confidence interval [CI]: 0.87 to 1.01) for macrolides, 1.04 (95% CI: 0.91 to 1.18) for tetracyclines, 1.02 (95% CI: 0.95 to 1.08) for penicillins, and 1.00 (95% CI: 0.82 to 1.22) for trimethoprim-sulfamethoxazole. Subjects with claims for quinolone antibiotics (HR = 1.17; 95% CI: 1.09 to 1.26) and cephalosporins (HR = 1.09; 95% CI: 1.02 to 1.16) had a slightly higher risk of stroke., Conclusion: Exposures to short courses of antibiotics are not associated with lower risk of ischemic stroke in patients aged 65 years and older.

Objectives: The resurgence of tuberculosis (TB) in NewYork City has been attributed to AIDS and immigration; however, the role of poverty in the epidemic is unclear. We assessed the relation between neighborhood poverty and TB at the height of the epidemic and longitudinally from 1984 through 1992., Methods: Census block groups were used as proxies for neighborhoods. For each neighborhood, we calculated TB and AIDS incidence in 1984 and 1992 with data from the Bureaus of Tuberculosis Control and AIDS Surveillance and obtained poverty rates from the census., Results: For 1992, 3,343 TB cases were mapped to 5,482 neighborhoods, yielding a mean incidence of 46.5 per 100,000. Neighborhood poverty was associated with TB (relative risk = 1.33; 95% confidence interval = 1.30, 1.36 per 10% increase in poverty). This association persisted after adjustment for AIDS, proportion foreign born, and race/ethnicity. Neighborhoods with declining income from 1980 to 1990 had larger increases in TB incidence than did neighborhoods with increasing income., Conclusions: Leading up to and at the height of the TB epidemic in New York City, neighborhood poverty was strongly associated with TB incidence. Public health interventions should target impoverished areas.

The purpose of this study was to evaluate intravenous (i.v.) azithromycin followed by oral azithromycin as a monotherapeutic regimen for community-acquired pneumonia (CAP). Two trials of i.v. azithromycin used as initial monotherapy in hospitalized CAP patients are summarized. Clinical efficacy is reported from an open-label randomized trial of azithromycin compared to cefuroxime with or without erythromycin. Bacteriologic and clinical efficacy results are also presented from a noncomparative trial of i.v. azithromycin that was designed to give additional clinical experience with a larger number of pathogens. Azithromycin was administered to 414 patients: 202 and 212 in the comparative and noncomparative trials, respectively. The comparator regimen was used as treatment for 201 patients; 105 were treated with cefuroxime alone and 96 were given cefuroxime plus erythromycin. In the comparative trial, clinical outcome data were available for 268 evaluable patients with confirmed CAP at the 10- to 14-day visit, with 106 (77%) of the azithromycin patients cured or improved and 97 (74%) of the comparator patients cured or improved. Mean i.v. treatment duration and mean total treatment duration (i.v. and oral) for the clinically evaluable patients were significantly (P < 0.05) shorter for the azithromycin group (3.6 days for the i.v. group and 8.6 days for the i.v. and oral group) than for the evaluable patients given cefuroxime plus erythromycin (4.0 days for the i.v. group and 10.3 days for the i.v. and oral group). The present comparative study demonstrates that initial therapy with i.v. azithromycin for hospitalized patients with CAP is associated with fewer side effects and is equal in efficacy to a 1993 American Thoracic Society-suggested regimen of cefuroxime plus erythromycin when the erythromycin is deemed necessary by clinicians.

The task assigned to the working group on Clinical Antimicrobial Trials for Primary and/or Secondary Prevention of Atherosclerotic Cardiovascular Disease was to evaluate the need for additional clinical antibiotic trials of a primary or secondary nature for the treatment of atherosclerotic heart disease and to suggest possible designs for future trials. In addition, the working group was to define the role of collaboration in answering research questions.

The purpose of this study was to use a health information network and innovative technology to coordinate tuberculosis care. An innercity medical center, a local health department, and a home care nurse service in northern Manhattan were used. The organizations were linked with computer networks. An automated decision support system with a natural language processor was used to detect tuberculosis cases and report them to the health department, and to select patients for respiratory isolation. Educational materials were placed on the World Wide Web and a Web-based kiosk. Home care nurses were outfitted with wireless pen-based computers, and data were relayed to the medical center. Automated tuberculosis case reporting resulted in time savings but not improved accuracy. Automated rules resulted in significant improvements in respiratory isolation. Kiosk educational materials were well-used. Wireless computing led to better access to information for both nurses and physicians, but not to reduction of workload. The key success element was recognition of critical priorities. It is concluded that innovative technology can facilitate the coordination of clinical care, public health, and home care., (Copyright 1999 Academic Press.)

Background: Correctly diagnosing tuberculosis (TB) in children is critical to provide appropriate treatment and to detect undiagnosed source cases. However, diagnosing TB in children may be difficult., Objective: We sought to determine whether Amplicor, a Food and Drug Administration-approved polymerase chain reaction (PCR) assay used to detect Mycobacterium tuberculosis in sputum and computerized tomography (CT) would facilitate the diagnosis of TB in children. We also examined the applicability of the Centers for Disease Control and Prevention clinical case definition for TB., Setting: A university-affiliated pediatric hospital in New York City., Subjects: From March, 1995, to November, 1997, 27 children < 15 years of age (mean age, 3.9 years) were evaluated for suspected TB., Results: M. tuberculosis was cultured from 5 of 76 (6.6%) gastric aspirate specimens, and PCR detected M. tuberculosis DNA in 3 (4.1%) of these specimens. There was poor correlation between culture and PCR because 6 specimens were discordant. CT scans were diagnostic of mediastinal or hilar adenopathy in 6 children with equivocal or negative chest radiographs and confirmed adenopathy in 8 others. Six children received alternative diagnoses., Conclusions: We conclude that the commercially available PCR technology had very limited utility in detecting M. tuberculosis from gastric aspirates, but CT scans were useful in assessing pediatric patients with suspected TB.

Obtaining encoded variables is often a key obstacle to automating clinical guidelines. Frequently the pertinent information occurs as text in patient reports, but text is inadequate for the task. This paper describes a retrospective study that automates determination of severity classes for patients with community-acquired pneumonia (i.e. classifies patients into risk classes 1-5), a common and costly clinical problem. Most of the variables for the automated application were obtained by writing queries based on output generated by MedLEE1, a natural language processor that encodes clinical information in text. Comorbidities, vital signs, and symptoms from discharge summaries as well as information from chest x-ray reports were used. The results were very good because when compared with a reference standard obtained manually by an independent expert, the automated application demonstrated an accuracy, sensitivity, and specificity of 93%, 92%, and 93% respectively for processing discharge summaries, and 96%, 87%, and 98% respectively for chest x-rays. The accuracy for vital sign values was 85%, and the accuracy for determining the exact risk class was 80%. The remaining 20% that did not match exactly differed by only one class.