Daptomycin is the first available agent from a new class of antibiotics, the cyclic lipopeptides, that has activity against a broad range of gram-positive pathogens, including organisms that are ...resistant to methicillin, vancomycin, and other currently available agents. Daptomycin (4 mg/kg intravenously iv every 24 h for 7–14 days) was compared with conventional antibiotics (penicillinase-resistant penicillins 4–12 g iv per day or vancomycin 1 g iv every 12 h) in 2 randomized, international trials involving 1092 patients with complicated skin and skin-structure infections. Among 902 clinically evaluable patients, clinical success rates were 83.4% and 84.2% for the daptomycin- and comparator-treated groups, respectively (95% confidence interval, -4.0 to 5.6). Among patients successfully treated with iv daptomycin, 63% required only 4–7 days of therapy, compared with 33% of comparator-treated patients (P < .0001). The frequency and distribution of adverse events were similar among both treatment groups. Overall, the safety and efficacy of daptomycin were comparable with conventional therapy.
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Background. The Shingles Prevention Study (SPS) demonstrated zoster vaccine efficacy through 4 years postvaccination. A Short-Term Persistence Substudy (STPS) demonstrated persistence of vaccine ...efficacy for at least 5 years. A Long-Term Persistence Substudy (LTPS) was undertaken to further assess vaccine efficacy in SPS vaccine recipients followed for up to 11 years postvaccination. Study outcomes were assessed for the entire LTPS period and for each year from 7 to 11 years postvaccination. Methods. Surveillance, case determination, and follow-up were comparable to those in SPS and STPS. Because SPS placebo recipients were offered zoster vaccine before the LTPS began, there were no unvaccinated controls. Instead, SPS and STPS placebo results were used to model reference placebo groups. Results. The LTPS enrolled 6867 SPS vaccine recipients. Compared to SPS, estimated vaccine efficacy in LTPS decreased from 61.1% to 37.3% for the herpes zoster (HZ) burden of illness (BOI), from 66.5% to 35.4% for incidence of postherpetic neuralgia, and from 51.3% to 21.1% for incidence of HZ, and declined for all 3 outcome measures from 7 through 11 years postvaccination. Vaccine efficacy for the HZ BOI was significantly greater than zero through year 10 postvaccination, whereas vaccine efficacy for incidence of HZ was significantly greater than zero only through year 8. Conclusions. Estimates of vaccine efficacy decreased over time in the LTPS population compared with modeled control estimates. Statistically significant vaccine efficacy for HZ BOI persisted into year 10 postvaccination, whereas statistically significant vaccine efficacy for incidence of HZ persisted only through year 8.
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SETTING: The World Health Organization recommends the use of isoniazid preventive therapy (IPT) for human immunodeficiency virus (HIV) infected patients with a positive tuberculin skin test (TST). ...However, due to concerns about the effectiveness of IPT in community health care settings
and the development of drug resistance, these recommendations have not been widely implemented in countries where tuberculosis (TB) and HIV co-infection is common. OBJECTIVE: To evaluate the effectiveness of IPT on survival and TB incidence among HIV-infected patients in Tanzania. DESIGN:
A cohort study nested within a randomized trial of HIV-infected adults with baseline CD4 counts of ≥ 200 cells/μ l was conducted to compare survival and incidence of active TB between TST-positive subjects who did or did not complete 6 months of IPT in the period 2001-2008. RESULTS:
Of 558 TST-positive subjects in the analytic cohort, 488 completed 6 months of IPT and 70 did not. Completers had a decrease in mortality compared to non-completers (HR 0.4, 95%CI 0.2-0.8). However, the protective effect of IPT on the incidence of active TB was non-significant (HR 0.6,
95%CI 0.3-1.3). CONCLUSION: Completion of IPT is associated with increased survival in HIV-infected adults with CD4 counts ≥ 200 cells/μ l and a positive TST.
Background. The causes of persistent bacteremia (PB) due to methicillin-resistant Staphylococcus aureus (MRSA) are poorly understood. This investigation examined potential associations between PB ...with key clinical features and several in vitro bacterial genotypic and phenotypic characteristics, in isolates from 1 institution. Methods. Pulsed-field gel electrophoresis (PFGE) relatedness, thrombin-induced platelet microbicidal protein (tPMP)-susceptibility phenotype, accessory gene regulator (agr) genotype and functionality (via δ-lysin production), and autolysis phenotypes were assessed in MRSA isolates from the bloodstream of 21 prospectively identified patients with PB (blood cultures positive after ⩾7 days of therapy) and of 18 patients with resolving bacteremia (RB) (sterile blood cultures within the first 2–4 days of therapy) due to MRSA. Results. The 2 groups had comparable baseline characteristics but differed in their clinical courses (e.g., endocarditis was more frequent in patients with PB than in those with RB 43% vs. 0%, respectively; P = .0016); isolates from patients with PB exhibited higher rates of (1) survival in vitro after exposure to tPMP (22.4 ± 14.8% vs. 11.6 ± 6.5%, respectively; P = .005); (2) defective δ-lysin production (71.4% vs. 38.9%, respectively; P = .057); (3) non-agr genotype II profile (100% vs. 77.8%, respectively; P = .037); and (4) overrepresentation of a specific PFGE genotype (85.7% vs. 44.4%, respectively; P = .015). Conclusions. Isolates from patients with PB differed from those in patients with RB, in several in vitro characteristics. Further studies will be necessary to define how these factors might affect clinical outcome.
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Clinical microbiologists are often asked to determine the relatedness of a group of bacterial isolates, that is, to type them. During the last decade, traditional methods of strain typing, such as ...bacteriophage typing and serotyping, have been supplemented or replaced in many laboratories with newer molecular methods, such as plasmid fingerprinting (43), ribotyping (40), PCR-based methods (45), and analysis of chromosomal DNA restriction patterns by pulsed-field gel electrophoresis (PFGE) (4, 14, 27). Although bacteriophage typing is still used in a number of large reference laboratories around the world for epidemiologic studies of Staphylococcus aureus (36) and serotyping continues to be a useful tool for epidemiologic surveillance of Salmonella species (30), there is a need for a method of strain typing that can be used to type a broader array of bacterial species. At present, PFGE comes closest to satisfying that need (3, 42). PFGE involves embedding organisms in agarose, lysing the organisms in situ, and digesting the chromosomal DNA with restriction endonucleases that cleave infrequently (14, 27). Slices of agarose containing the chromosomal DNA fragments are inserted into the wells of an agarose gel, and the restriction fragments are resolved into a pattern of discrete bands in the gel by an apparatus that switches the direction of current according to a predetermined pattern. The DNA restriction patterns of the isolates are then compared with one another to determine their relatedness. Currently, there are no standardized criteria for analyzing the fragment patterns. Consequently, different investigators viewing the same PFGE results may come to quite different conclusions as to which isolates should be designated as outbreak related and which should be designated as non-outbreak related. This guest commentary proposes a set of guidelines for interpreting DNA restriction patterns generated by PFGE. The authors are investigators from the United States who, over the last several years, have correlated epidemiologic data from dozens of outbreaks with strain typing results produced by PFGE. These guidelines are intended to be used by clinical microbiologists in hospital laboratories to examine relatively small sets of isolates (typically, less than or equal to 30) related to putative outbreaks of disease. In an effort to make PFGE more easily understood and accessible as a typing method, the use of statistical methods and equipment to digitize patterns has been avoided. Such methods may be appropriate for larger collections of isolates studied in reference laboratories, but they are neither feasible nor necessary for laboratories that will be confronted primarily with short-term outbreaks.
BACKGROUND: Disseminated tuberculosis (TB) is a major cause of death in patients with the acquired immune-deficiency syndrome (AIDS), but its pathogenesis and clinical features have not been defined ...prospectively.METHODS: Human immunodeficiency virus (HIV) infected adults with a
CD4 count ≥ 200 cells/μl and bacille Calmette-Guérin scar underwent immunologic evaluation and subsequent follow-up.RESULTS: Among 20 subjects who developed disseminated TB, baseline tuberculin skin tests were ≥15 mm in 14 (70%) and lymphocyte proliferative responses to
Mycobacterium tuberculosis were positive in 14 (70%). At the time of diagnosis, fever ≥2 weeks plus ≥5 kg weight loss was reported in 16 (80%) patients, abnormal chest X-rays in 7/17 (41%), and positive sputum cultures in 10 (50%); median CD4 count was 30 cells/μl (range 1-122).
By insertion sequence (IS) 6110 analysis, 14 (70%) blood isolates were clustered and 3/8 (37%) concurrent sputum isolates represented a different strain (polyclonal disease). Empiric TB treatment was given to eight (40%) patients; 11 (55%) died within a month.CONCLUSIONS: Disseminated
TB in HIV occurs with cellular immune responses indicating prior mycobacterial infection, and IS6110 analysis suggests an often lethal combination of reactivation and newly acquired infection. Control will require effective prevention of both remotely and recently acquired infection,
and wider use of empiric therapy in patients with advanced AIDS and prolonged fever.
To determine whether a multiple-dose series of an inactivated whole cell mycobacterial vaccine, Mycobacterium vaccae, can prevent HIV-associated tuberculosis.
The DarDar trial was a randomized, ...placebo-controlled, double-blind trial. The study was carried in an outpatient facility in Dar es Salaam, Tanzania. HIV-infected patients with CD4 cell counts of at least 200 cells/microl and a Bacille Calmette-Guérin scar were chosen for the study. The intervention was carried out by random 1:1 assignment to five intradermal doses of M. vaccae or placebo. Tuberculin skin tests were performed, and patients with reactions of at least 5 mm were administered isoniazid for 6 months. The main outcome measures were disseminated (primary endpoint), definite, and probable tuberculosis (secondary endpoints).
Two thousand thirteen individuals were randomized (1006 to M. vaccae, 1007 to placebo) and followed every 3 months for a median of 3.3 years. The trial was terminated early because of slow accrual of cases of disseminated tuberculosis and significant protection against definite tuberculosis. Hazard ratios were disseminated tuberculosis 0.52 (95% confidence interval 0.21-1.34; seven cases in M. vaccae, 13 cases in placebo; log-rank P = 0.16), definite tuberculosis 0.61 (95% confidence interval 0.39-0.96; 33 cases in M. vaccae, 52 cases in placebo; P = 0.03), and probable tuberculosis 1.17 (95% confidence interval 0.76-1.80; 48 cases in M. vaccae, 40 cases in placebo; P = 0.46). Immunization was well tolerated, with no adverse effect on CD4 cell count or HIV viral load, and no increase in the rate of serious adverse events.
Administration of a multiple-dose series of M. vaccae to HIV-infected adults with childhood Bacille Calmette-Guérin immunization is safe and is associated with significant protection against definite tuberculosis. These results provide evidence that immunization with a whole cell mycobacterial vaccine is a viable strategy for the prevention of HIV-associated tuberculosis.
Four patients on a surgical ward develop postoperative pneumonia due to Klebsiella pneumoniae. Is this an outbreak? A child recently treated for an Escherichia coli urinary tract infection returns ...with another. Is this a relapse due to the original organism or a new infection due to a different strain? Several cultures of blood from a man with a prosthetic heart valve yield only Staphylococcus epidermidis. The isolates have different antibiotic susceptibilities. Do they represent a single infecting strain or multiple contaminants? Each of these situations presents the medical practitioner with a problem that involves reliably differentiating multiple bacterial isolates or establishing that the isolates are identical. In recent years, investigations of epidemiology and pathogenesis have utilized a wide variety of techniques derived from immunology, biochemistry, and genetics; these studies are often referred to collectively as molecular epidemiology. This commentary gives an overview of the systems available for typing microorganisms and describes the strengths and weaknesses of each. We focus almost exclusively on the analysis of bacteria, as molecular techniques relating to fungi are just emerging and studies of viruses are generally restricted to specific research settings.
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Small-colony variants (SCVs) of Staphylococcus aureus were cultured from five patients with persistent and relapsing infections. All five SCV strains were nonhemolytic and nonpigmented and grew very ...slowly on routine culture media in an ambient atmosphere. In several instances, these phenotypic characteristics led to the initial misidentification of the organisms in the clinical microbiology laboratory. All four strains available for further analysis were shown to be auxotrophs that reverted to normal growth and morphology in the presence of menadione, hemin, and/or a CO2 supplement. Similarly, these isolates were resistant to aminoglycosides under routine conditions but susceptible in the presence of the metabolic supplements. For two patients, the large and small colony forms isolated concurrently were indistinguishable when analyzed by pulsed field gel electrophoresis and thus represented phenotypic variants within individual clones. We propose a model relating the phenotypic characteristics of S. aureus SCVs with the clinical pattern of persistent and relapsing infection.
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