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Combination antiretroviral therapy (cART) can cause metabolic toxicities. How cART simplification to dual or monotherapies affects metabolic markers is unknown. We analyzed the metabolic effects of cART simplification to dolutegravir (DTG) monotherapy in the randomized clinical DOMONO (DOlutegravir MONOtherapy for HIV) trial including HIV-positive participants. Renal function, Framingham risk score (FRS), inflammation, and bone mineral density (BMD) with trabecular bone score (TBS) were measured during 48 weeks after simplification. The changes at 48 weeks by on-treatment analyses overall and for prior tenofovir disoproxil fumarate (TDF) exposure were analyzed separately, using Bonferroni corrected alpha (p = 0.00096). Ninety-five patients initiated DTG monotherapy, including 80 discontinuing TDF. At week 48, the switch to DTG monotherapy resulted in an expected −7.8 ml/min estimated glomerular filtration decline. In patients on prior TDF, proteinuria improved (p

Background: The high genetic barrier to resistance of dolutegravir might allow for its use as maintenance monotherapy in patients with HIV. We investigated whether dolutegravir monotherapy was non-inferior to combination antiretroviral therapy (ART) for maintaining virological suppression in patients with HIV-1 infection successfully treated with combination ART.Methods: We did this open-label, phase 2, randomised non-inferiority trial at two medical centres in the Netherlands. Eligible patients (aged ≥18 years) were on combination ART, had been virologically suppressed (HIV RNA vs 50 000–99 999 copies per mL). Investigators and patients were not masked to group allocation. The primary endpoint was the proportion of patients with plasma HIV RNA viral loads of less than 200 copies per mL at week 24, with a non-inferiority margin of 12%. We did analyses in the on-treatment and intention-to-treat populations. This trial is registered with ClinicalTrials.gov, NCT02401828.Findings: Between March 10, 2015, and Feb 4, 2016, we randomly assigned 51 patients to the immediate switch group and 53 patients to the delayed switch group. One patient who received immediate monotherapy discontinued treatment at week 12 because of disturbed sleep. At week 24, dolutegravir monotherapy was non-inferior to combination ART, with plasma HIV RNA loads of 200 copies per mL or higher observed in 2% (1/50) of patients in the immediate switch group and in no patients in the delayed switch group (difference 2%, 95% CI-5 to 12). Of patients assigned to the delayed switch group, 47 (89%) switched to dolutegravir monotherapy at week 24, two (4%) of whom subsequently discontinued monotherapy because of headache (n=1) and disturbed sleep (n=1). Eight (8%) of the 95 patients who remained on dolutegravir monotherapy had virological failure; all had therapeutic plasma concentrations of dolutegravir. In three (38%) of the eight patients, mutations associated with resistance were detected in the integrase gene. According to a predefined stopping rule, detection of these mutations led to premature study discontinuation.Interpretation: Dolutegravir monotherapy was non-inferior to combination ART at 24 weeks. However, virological failure continued to occur thereafter and led to dolutegravir resistance. Dolutegravir should not be used as maintenance monotherapy.

P>The Staphylococcus aureus immune evasion cluster (IEC), located on beta-haemolysin-converting bacteriophages (beta C-Theta s), encodes the immune-modulating proteins chemotaxis inhibitory protein, staphylococcal complement inhibitor (SCIN), staphylococcal enterotoxin A and staphylokinase. Its precise role in S. aureus colonization is unclear. We studied the presence of the IEC-carrying bacteriophages in human and animal S. aureus isolates, using PCR for the gene encoding SCIN (scn). Human isolates were obtained by collecting serial nasal swabs from 21 persistent carriers. S. aureus strains from 19 (90%) persistent carriers contained an IEC that was present and indistinguishable in 95% of cases at all five sampling moments over a 3-month period. Of the 77 infectious animal strains included in the study, only 26 strains (34%) were IEC-positive. Integration of these IEC-positive strains into an amplified fragment length polymorphism genotype database showed that 24 of 53 (45%) strains were human-associated and only two of 24 (8%) were 'true' animal isolates (p < 0.001). The high prevalence and stability of IEC-carrying beta C-Theta s in human strains suggested a role for these beta C-Theta s in human nasal colonization. To test this hypothesis, 23 volunteers were colonized artificially with S. aureus strain NCTC 8325-4 with or without the IEC type B-carrying beta C-Theta 13. Intranasal survival was monitored for 28 days after inoculation. The strain harbouring beta C-Theta 13 was eliminated significantly faster (median 4 days; range 1-14 days) than the strain without beta C-Theta 13 (median 14 days; range 2-28 days; p 0.011). In conclusion, although IEC-carrying beta C-Theta s are highly prevalent among human colonizing S. aureus strains, they are not essential in the first stages of S. aureus nasal colonization.

Background. Persistent nasal carriers have an increased risk of Staphylococcus aureus infection, whereas intermittent carriers and noncarriers share the same low risk. This study was performed to provide additional insight into staphylococcal carriage types. Methods. Fifty-one volunteers who had been decolonized with mupirocin treatment and whose carriage state was known were colonized artificially with a mixture of S. aureus strains, and intranasal survival of S. aureus was compared between carriage groups. Antistaphylococcal antibody levels were also compared among 83 carriage-classified volunteers. Results. Persistent carriers preferentially reselected their autologous strain from the inoculum mixture (P = .02). They could be distinguished from intermittent carriers and noncarriers on the basis of the duration of postinoculation carriage (154 vs. 14 and 4 days, respectively; P = .017, by log-rank test). Cultures of swab samples from persistent carriers contained significantly more colony-forming units per sample than did cultures of swab samples from intermittent carriers and noncarriers (P = .004). Analysis of serum samples showed that levels of immunoglobulin G and immunoglobulin A to 17 S. aureus antigens were equal in intermittent carriers and noncarriers but not in persistent carriers. Conclusions. Along with the previously described low risk of infection, intermittent carriers and noncarriers share similar S. aureus nasal elimination kinetics and antistaphylococcal antibody profiles. This implies a paradigm shift; apparently, there are only 2 types of nasal carriers: persistent carriers and others. This knowledge may increase our understanding of susceptibility to S. aureus infection.

Although Staphylococcus aureas is a bacterial species of medical significance, only approximately 30% of all humans carry staphylococcal cells persistently but asymptomatically in their nasopharynx and/or other body sites. This goes largely unnoticed by the host, which shows that in the natural situation the human ecosystem is hospitable or at least receptive to the bacteria and that by a process of co-evolution this has lead to a state of mutual acceptance or tolerance. However, upon disturbance of this balanced. neutral state, localized or disseminated invasive infection can occur. Unfortunately, the events leading to infection are still largely unknown and especially the causal events leading to the transition from colonization to infection are ill-defined in vivo. Whether certain genotypes of S. aureus are more prone to colonise and/or infect humans is still quite heavily debated. The genetic population Structure of S. aureus has been largely solved by using a number of different DNA polymorphism-interrogating laboratory methods. However, even this major effort has not (yet) revealed major Cities with respect to colonisation and infection potency of the clonal lineages that were thus identified, except for the fact that certain lineages are highly epidemic. The overall Picture is that in principle all S. aureus strains can become invasive given the proper circumstances. What these, primarily host-defined Circumstances are is still enigmatic. However, a large variety of staphylococcal virulence and colonization factors have been identified as well as a number of host' colonisation and infection Susceptibility traits. How these are specifically involved in colonisation and infection has been experimentally Substantiated in only a limited number of cases. The present review paper will explore the relevance of these and other, for instance environmental factors that define the colonisation or infection state in humans. When the nature of these states would be known in more detail, this knowledge could be used to design novel and empirical, knowledge-driven means of preventing colonisation from proceeding into S. aureus infection. (c) 2008 Elsevier B.V. All rights reserved.

The aim of this study was to determine whether polymorphisms of the glucocorticoid receptor gene, influencing glucocorticoid sensitivity, are associated with persistent nasal carriage of Staphylococcus aureus. Two nasal swab cultures were obtained from each of 2,929 participants. Subjects were classified as persistent carriers (n=563) if both cultures were positive. GG homozygotes of the exon 9beta polymorphism were associated with a 68% reduced risk of persistent S. aureus nasal carriage, whereas carriers of the codon 23 lysine allele displayed an 80% increased risk. Thus, genotype-dependent variation in the sensitivity to glucocorticoids is associated with tolerance toward staphylococcal nasal colonization.

Persistent (not intermittent) nasal carriage of Staphylococcus aureus is the determinant of CPD-related infections. Background We investigated the impact of staphylococcal carriage among patients on continuous peritoneal dialysis (CPD) in a university hospital. Methods Patients were screened for Staphylococcus aureus carriage and categorized as persistent, intermittent, or non– S. aureus nasal carriers. Patients were subsequently recultured every 12 weeks for S. aureus and coagulase negative staphylococcal (CoNS) carriage, and followed-up for CPD-related infections and antibiotic resistance. Results Fifty-two patients were included: 20 peristent, 10 intermittent, and 22 non– S. aureus carriers. Only persistent S. aureus carriage was significantly associated with an increased risk for all CPD-related infections [incidence rate ratio (IRR) 3.52 (95% CI: 2.56–4.85)], exit site infections [IRR 5.59 (95% CI: 3.50–8.92)], and peritonitis [IRR 2.19 (95% CI: 1.39–3.45)], as well as increased antibiotic use [IRR 3.43 (95% CI: 2.50–4.72)], including vancomycin [IRR 2.15 (95%: 2.13–2.16)]. No vancomycin-resistant S. aureus strains were detected. However, eight (2%) out of 407 CoNS strains isolated were vancomycin intermediately susceptible. In all five patients (four persistent and one intermittent carriers) concerned, this was significantly related to a higher antibiotic (including vancomycin) usage [IRR 2.65 (95% CI: 1.82–3.84)]. Conclusion Persistent—but not intermittent— S. aureus nasal carriage is the major determinant of CPD-related infections, and is associated with a significantly higher consumption of antibiotics, including vancomycin. The highly diverse population of CoNS appears to be the prime reservoir of staphylococcal vancomycin resistance. Accurate determination of the S. aureus nasal carriage state of CPD patients is essential to better target intervention strategies to prevent CPD-related infections.

The vitamin D endocrine system has been shown to influence the immune response and polymorphisms in the vitamin D receptor (VDR) gene have been associated with susceptibility to infectious diseases. We determined if the Cdx2, FokI and BsmI-ApaI-TaqI polymorphisms in the VDR gene were associated with nasal carriage of Staphylococcal aureus. We defined the S. aureus nasal carriage status (persistent, intermittent or non-carriage) for a group of more that 2000 elderly volunteers. The prevalence of persistent S. aureus nasal carriage was 18%, which was, however, not associated with any of the variant VDR genotypes. Our study into genetic determinants of S. aureus carriage patterns is the largest in the field, but still we found no association between VDR gene variation and S. aureus nasal carriage.

We determined the prevalence of renal impairment and possible HIV-associated nephropathy (HIVAN) in adults with World Health Organization (WHO) stages I or II HIV, presenting to the antiretroviral therapy (ART) clinic in a central hospital in Malawi. We enrolled 526 ART-naïve subjects, 67% women, median age 34 (17–73) years and mean CD4 count 305 (3–993) cells/μL. Blood pressure, weight, urine dipstick and microscopy, CD4 cell count and serum creatinine were measured. Creatinine clearance (CrCL) was estimated using the Cockcroft–Gault equation. Possible HIVAN was diagnosed based on levels of proteinuria and CrCl. In all, 23.3% had proteinuria (≥1+). 57.4% had reduced CrCl (

The prevalence of group B streptococcus (GBS) carriage varies strongly with geographical region. A study was done to determine the prevalence of GBS in women in Maputo, Mozambique. The method used was a rectovaginal swab which was taken from women between 35 and 37 weeks of pregnancy who visited the clinic for antenatal consultation. GBS was cultured from 2 out of 113 samples, yielding a prevalence of 1.8% (95% Cl: 0.0-4.0). In conclusion, the prevalence of GBS carriage among pregnant women in Maputo, Mozambique was low.

It has been shown that persistent Staphylococcus aureus nasal carriage results in increased bacterial dispersal and a higher risk of infection compared to non-or-intermittent S. aureus carriage. Although many studies investigated S. aureus nasal carriage in HIV patients, none compared persistent carriage to non-persistent carriage nor were studies performed in the HAART era. We investigated the host-microbe interplay of persistent S. aureus nasal carriage in HIV-infected patients by studying host determinants of persistent carriage as well as the genetic structure of S. aureus strains isolated. We compared this genetic structure with the previously determined population structure of S. aureus isolates obtained from healthy individuals. Between February 2004 and June 2005 all HIV patients visiting the outpatient department of Erasmus MC (Rotterdam, The Netherlands) were asked to participate in this study. Participants were interviewed and screened for persistent S. aureus carriage using two semi-quantitative nasal swab cultures. For 443 patients two cultures were available, 131 (29.6%) were persistent carriers, which is significantly higher as compared to healthy individuals from the same geographic region (17.6%; P < 0.0001). Male sex (odds ratio [OR], 2.22; 95% confidence interval [CI], 1.32-3.73), current smoking (OR, 0.58; 95% CI, 0.38-0.90), Pneumocystis jiroveci pneumonia (PCP) prophylaxis (OR, 0.39; 95% CI, 0.16-0.97) and antiretroviral therapy (OR, 0.61; 95% CI, 0.38-0.98) were independent determinants of persistent carriage. Only two strains were mecA positive (1.2%) and no PVL positive strains were detected. The population structure of S. aureus strains isolated from HIV patients appeared to be strongly overlapping with that of S. aureus isolates from healthy individuals. (C) 2007 Elsevier Masson SAS. All rights reserved.

The epidemiology and risks of Staphylococcus aureus carriage in continuous peritoneal dialysis (CPD) patients was studied in a single tertiary-care institution. On outpatient visits samples for culture were routinely taken prospectively from the CPD catheter exit site and the vestibulum nasi. Seventy-five patients with at least one culture positive for S. aureus in this period were included: 43 had genotypically identical S. aureus strains in over 80% of the cultures and were classified as persistent carriers; 32 were intermittent carriers. Persistent carriage was associated with a threefold higher risk for CPD-related infections and sixfold higher rates of vancomycin consumption compared to those for the intermittent carriers. No methicillin or vancomycin resistance was detected.

Staphylococcus aureus is a frequent cause of infections in both the community and hospital. Worldwide, the increasing resistance of this pathogen to various antibiotics complicates treatment of S aureus infections. Effective measures to prevent S aureus infections are therefore urgently needed. It has been shown that nasal carriers of S aureus have an increased risk of acquiring an infection with this pathogen. The nose is the main ecological niche where S aureus resides in human beings, but the determinants of the carrier state are incompletely understood. Eradication of S aureus from nasal carriers prevents infection in specific patient categories-eg, haemodialysis and general surgery patients. However, recent randomised clinical trials in orthopaedic and non-surgical patients failed to show the efficacy of eliminating S aureus from the nose to prevent subsequent infection. Thus we must elucidate the mechanisms behind S aureus nasal carriage and infection to be able to develop new preventive strategies. We present an overview of the current knowledge of the determinants (both human and bacterial) and risks of S aureus nasal carriage. Studies on the population dynamics of S aureus are also summarised.

Objective: To test the hypothesis that fusidic acid would not increase the treatment effect of disinfecting with povidone-iodine alone in children with impetigo. Design: Randomised placebo controlled trial. Setting: General practices in Greater Rotterdam. Participants: 184 children aged 0-12 years with impetigo. Main outcome measures: Clinical cure and bacterial cure after one week. Results: After one week of treatment 55% of the patients in the fusidic acid group were clinically cured compared with 13% in the placebo group (odds ratio 12.6, 95% confidence interval 5.0 to 31.5, number needed to treat 2.3). After two weeks and four weeks the differences in cure rates between the two groups had become smaller. More children in the placebo group were non-compliant (12 v 5) and received extra antibiotic treatment (11 v 3), and more children in the placebo group reported adverse effects (19 v 7). Staphylococcus aureus was found in 96% of the positive cultures; no strains were resistant to fusidic acid. Conclusions: Fusidic acid is much more effective than placebo (when both are given in combination with povidone-iodine shampoo) in the treatment of impetigo. Because of the low rate of cure and high rate of adverse events in the placebo group, the value of povidone-iodine in impetigo can be questioned. What is already known on this topic Impetigo is the most common skin infection in children Fusidic acid, which is advocated as topical treatment in several countries, has never been investigated in a placebo controlled study What this study adds In combination with povidone-iodine, treatment with fusidic acid is much more effective than placebo None of the strains of Staphylococcus aureus isolated at baseline showed resistance to fusidic acid The value of treatment with povidone-iodine alone can be questioned