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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

Objectives The dolutegravir/valproic acid drug–drug interaction (DDI) is suggested to be caused by protein displacement. Here, we assess the underlying mechanism. Methods Participants in a randomized controlled trial investigating valproic acid as an HIV latency reversing agent were recruited in a predefined pharmacokinetic substudy if they were on once-daily 50 mg dolutegravir-containing combination ART (cART) for >12 months with a plasma HIV-RNA Results Six of 10 participants on dolutegravir were randomized to receive valproic acid. During 14 days of valproic acid treatment, the GM total dolutegravir concentration decreased sharply from 1.36 mg/L on day 0 to 0.85, 0.31 and 0.20 mg/L on days 0, 1, 7 and 14, respectively, while total dolutegravir concentrations in the controls remained comparable during the same period: 1.27–1.49 mg/L. We observed a parallel increase in unbound dolutegravir fractions ranging from 0.39% to 0.58% during valproic acid administration, compared with 0.25% to 0.28% without valproic acid. Unbound dolutegravir concentrations were above the established in vitro EC90 value for unbound dolutegravir in 85% of the tested samples. Conclusions This study confirms protein displacement as the main mechanism for this DDI, although additional mechanisms might be involved too. If dolutegravir is taken with food, this DDI is probably not clinically relevant.

Background HIV-1-infected patients can be superinfected with additional HIV-1 variants. Therapy failure can be the consequence of an infection with a resistant strain. Methods A patient was diagnosed with a recent HIV-1 infection in April 2005 and subsequently clinically monitored. HIV-1 evolution was studied by population sequencing of the first 984 bases of the pol gene as well as 454 ultra-deep pyrosequencing (UDPS) of parts of the pol and env genes. Results The patient was diagnosed with a wild-type HIV-1 strain, but experienced rapid virological failure after initiating a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based treatment regimen 3 years later. Population sequencing and UDPS revealed the presence of a second HIV-1 strain with a Y188L NNRTI resistance mutation in a sample obtained shortly prior to initiation of therapy. Phylogenetic analyses showed that the two HIV-1 strains were genetically distinct, providing evidence for superinfection. Conclusions The virological treatment failure in this patient was probably due to the superinfection with an NNRTI-resistant HIV-1 variant. Superinfection with drug-resistant strains can undermine HIV-1 treatment regimens selected on the basis of resistance testing at diagnosis. Patients, especially in high-risk groups, as well as their clinicians, should be aware of the risks and dangers of superinfections.

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.

A systematic review was performed to determine the effectiveness of different approaches for eradicating methicillin-resistant Staphylococcus aureus carriage. Twenty-three clinical trials were selected that evaluated oral antibiotics (7 trials), topically applied antibiotics (12 trials), or both (4 trials). Because of clinical heterogeneity, quantitative analysis of all studies was deemed to be inappropriate, and exploratory subgroup analyses were performed for studies with similar study populations, methods, and targeted bacteria. The estimated pooled relative risk of treatment failure 1 week after short-term nasal mupirocin treatment, compared with placebo, was 0.10 (range, 0.07–0.14). There was low heterogeneity between study outcomes, and effects were similar for patients and healthy subjects, as well as in studies that included only methicillin-susceptible S. aureus carriers or both methicillin-susceptible S. aureus and methicillin-resistant S. aureus carriers. The development of drug resistance during treatment was reported in 1% and 9% of patients receiving mupirocin and oral antibiotics, respectively. Short-term nasal application of mupirocin is the most effective treatment for eradicating methicillin-resistant S. aureus carriage, with an estimated success of rate of 90% 1 week after treatment and ∼60% after a longer follow-up period. Colonization is an important step in the pathogenesis of Staphylococcus aureus infection and is instrumental in the nosocomial epidemiology of these bacteria. Approximately 20% of the general population is persistently colonized with S. aureus, most frequently in the anterior nares, although other body sites, such as the perineum and throat, may also be colonized. Another 30% of the general population is intermittently colonized, and the remaining 50% appear not to be susceptible, for unknown reasons, to S. aureus carriage [1]. Methicillin-resistant S. aureus (MRSA) has become endemic in health care institutions worldwide, with up to 70% of invasive S. aureus infections having resistance [2–5], and most patients who develop drug-resistant S. aureus infection will have been colonized prior to infection. The half-life of MRSA carriage has been reported to be as long as 40 months in individuals who do not receive treatment [6].

Staphylococcus aureus colonization of the human nares predisposes to sometimes severe auto-infection. To investigate whether genetic polymorphism affects the S. aureus carriage status, sequence variation in alpha-defensin and beta-defensin, and mannose-binding lectin (MBL) genes were determined for a group of volunteers (n=109) with known S. aureus nasal carriage status. DEFA1/3 expression was measured in a subset of the volunteers (n=32). None of the single nucleotide polymorphisms studied could clearly distinguish the (non) carriage groups. S. aureus carriers differed from non-carriers in baseline level of HNP1-3 peptide production (median: 218 versus 89mug/ml, P=0.016). No association between HNP1-3 levels and the individual sequence polymorphisms was documented. The combined copy numbers of DEFA1/A3 genes ranged from 5 to 23 per diploid genome. A linear correlation between combined copy numbers and HNP1-3 peptide concentrations in nasal secretions of non-carriers was noted (r(2)=0.8991). DEFA3 gene was absent in 25% of the individuals. MBL haplotype A was overrepresented in persistent S. aureus carriers (87% vs. 67%; P=0.038). In conclusion, defensin gene polymorphism, both in sequence and in gene copy numbers, does not seem to be involved in S. aureus carriage predisposition. However, MBL haplotypes do so significantly. Baseline HNP1-3 production is more the consequence of S. aureus colonization than a reason for the (non) carrier status.

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.

Persistent nasal carriers and noncarriers of Staphylococcus aureus were inoculated with a mixture of different S. aureus strains. The majority of noncarriers and nearly all persistent carriers returned to their original carrier state after artificial inoculation. Furthermore, the majority of persistent carriers tested positive again for their original resident strain. Using a human nasal inoculation model, we here demonstrate that the human factor is an important determinant of S. aureus nasal carriage.

Coagulase negative staphylococci (CoNS) are a main cause of catheter related infections (CRI). Earlier studies (1994-1996) revealed a high incidence of CRI (6 per 1000 catheter days) among neutropenic hemato-oncologic patients in the Erasmus MC Hematology Department (Rotterdam, The Netherlands). This was mainly explained by expansion of two methicillin resistant Staphylococcus epidermidis (MRSE) clones (Nouwen et al., J. Clin. Microbiol. 36 (1998) 2696-2702). In a new, 16-bed unit in the same institution, we investigated the effect of strict clinical isolation measures on the incidence of CRI. During two 6-month screening periods (period I: April 1998-December 1998 and period II: April 1999-October 1999) all patients receiving a central venous catheter were prospectively monitored for the development of CRI. During period I every visitor of the cubicles had to wear hair caps, masks, gowns and gloves. During period II these procedures were abolished, but hands were cleansed using alcohol and masks were worn during both periods in case of coughing and sneezing. All CoNS strains isolated from blood cultures were genetically classifies by pulsed field gel electrophoresis (PFGE). The incidence of CRI during period I was 13.0 per 1000 catheter days, in comparison to 9.6 in period II (P=0.84). During this latter period, 19 CRI were diagnosed, 14 catheter related bacteremia episodes (CRB) and five local infections. Seventy-two percent (n=9) of CRB were due to a CoNS. The mean catheter survival until appearance of a CRI increased from 43 days during period I to 78 days in period II (P=0.39). The mean catheter survival until infection related removal was increased from 43 days to 133 days (P=0.12). During period I less experienced intervention radiologists introduced the catheters, which may have limited the efficacy of the strict hygiene measures. Thus, abolishing strict isolation precautions had no negative effect on the incidence of CRI. After genotyping of 38 MRSE strains isolated from blood and central venous catheter cultures of 12 patients in period II, eight PFGE types were found. Three types were found in more than one patient, but based on epidemiological data patient-to-patient spread could not be proven. No genotypic identity between patient and personnel CoNS isolates was shown and the two major clonal types that were present between 1994 and 1996 were not encountered. However, from December 1998 onwards new MRSE clones could be identified (types E and J). In conclusion, despite a constant rate of CRI and implementation of optimal patient care, clonal spread of MRSE strains was not prevented by strict hygiene measures.

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.

The Staphylococcus aureus enterotoxin gene cluster, egc , was detected in isolates from healthy individuals and in those from patients with bacteremia. The egc genes cooccur and are slightly enriched in strains from healthy carriers (present in 63.7% of carriage-associated isolates versus 52.9% of invasive isolates; P = 0.03). Multilocus sequence typing revealed that successful staphylococcal clones usually harbor the egc locus.

Item does not contain fulltext BACKGROUND: Staphylococcus aureus is capable of persistently colonizing the vestibulum nasi. We hypothesized that polymorphisms in host inflammatory response genes and genetic variation in S. aureus contribute to susceptibility to S. aureus carriage and infection. METHODS: The prevalence of persistent nasal carriage of S. aureus in 3851 participants aged 61-101 years was 18% (678 of 3851 participants), whereas 73% of volunteers (2804 of 3851) were not colonized. A total of 1270 individuals had boils. Polymorphisms in TNFA (C -863T), IL4 (C -542T), CFH (Tyr402His), and CRP (C1184T, C2042T, and C2911G) were determined. Genetic similarity among 428 S. aureus isolates was determined by use of amplified fragment length polymorphism analysis (AFLP)-mediated genotyping. RESULTS: The IL4 -524 C/C host genotype was associated with an increased risk of persistent S. aureus carriage, irrespective of S. aureus AFLP genotype. The CRP haplotype 1184C; 2042C; 2911C was overrepresented in individuals who were not colonized . In individuals with boils, carriers of the CFH Tyr402 variant, and the CRP 2911 C/C genotype were overrepresented. CONCLUSION: Persistent carriage of S. aureus is influenced by genetic variation in host inflammatory response genes. As would be expected in multifactorial host-microbe interactions, these effects are limited. Interestingly, host genotype was associated with the carriage of certain S. aureus genotypes. Apparently, a close interaction between host and bacterial determinants are prerequisites for long-term colonization.

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.

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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.

Invasive Staphylococcus aureus infections are frequently associated with bacteraemia. To support clinical decisions on antibiotic therapy, there is an urgent need for reliable markers as predictors of infection outcome. In the present study in mice, bacteraemia was established by intravenous inoculation of a clinical S. aureus isolate at the LD50 inoculum. As potential biomarkers for fatal outcome, blood culture (qualitative and quantitative), serum levels of C-reactive protein (CRP), as well as 31 selected cytokines and chemokines were assessed during the first three days of infection. A positive S. aureus blood culture, the quantitative blood culture, CRP levels, and levels of eight cytokines were indicative for the presence of S. aureus bacteraemia. However, only tumor necrosis factor (TNF) α, interleukin (IL) 1α, and keratinocyte chemoattractant (KC; a functional homologue of human IL-8) were each significantly elevated in eventually non-surviving infected mice versus eventually surviving infected mice. In severe S. aureus bacteraemia in mice, TNF-α, IL-1α, and KC are biomarkers predicting fatal outcome of infection. KC was a biomarker elevated irrespective the progression of infection, which is very interesting regarding clinical application in view of the heterogeneity of patients experiencing bacteraemia in this respect.