The dolutegravir/valproic acid drug-drug interaction is primarily based on protein displacement.

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 <50 copies/mL (trial registration: ClinicalTrials.gov NCT03525730). Participants were randomized to receive 30 mg/kg/day valproic acid orally (divided into two equal doses) for 14 days or not. Total and unbound dolutegravir concentrations were measured on day 0 (before intake of valproic acid and 6 h after intake of valproic acid) and on days 1, 7, 14 and 42. Intra- and inter-subject dolutegravir concentrations and geometric means (GMs) were evaluated. 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.

Prevalence of nasal methicillin-resistant Staphylococcus aureus colonization in healthcare workers in a Western Australian acute care hospital.

Due to a longstanding comprehensive "search and destroy policy", methicillin-resistant Staphylococcus aureus (MRSA) is not endemic in Western Australian (WA) acute care hospitals. As the prevalence of MRSA in the community has increased, healthcare workers (HCW) are at risk of importing MRSA into hospitals. We aimed to determine the prevalence of and risk factors for nasal MRSA colonization in our HCW population. A period prevalence study was conducted at an 850-bed tertiary hospital. Basic demographics and a nasal swab were obtained. A total of 1,542 HCWs employed in our centre were screened for MRSA, of whom 3.4% (n = 52) were colonized. MRSA colonization was more common in patient care assistants (6.8%) and nurses (5.2%) than in allied health professionals (1.7%) and doctors (0.7%) (p < 0.01). Working in "high-risk" wards that cared for MRSA colonized/infected patients was the strongest risk factor for HCW MRSA colonization (p < 0.001). ST1-IV and ST78-IV (the most common community clones in the region) were the most frequently identified clones. In conclusion, MRSA colonization of HCWs occurs primarily in HCWs caring for patients colonized or infected with MRSA. Surveillance screening of HCWs should be regularly performed on wards with patients with high MRSA colonization prevalence to prevent further spread in the hospital.

The prevalence of renal impairment among adults with early HIV disease in Blantyre, Malawi.

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 (< 90 mL/minute): 18.8% had moderate (CrCl 30-59 mL/minute) and 2.2% severe (CrCl <30 mL/minute) renal dysfunction. Extrapolating from renal biopsy studies that confirmed HIVAN, the proportion of patients with HIVAN in our clinic ranges from 1.8-21.2%. We conclude that renal impairment was common, though rarely severe, among HIV-infected adults with clinically non-advanced HIV disease. Renal dysfunction has been demonstrated to be a risk factor for (early) mortality. These results are relevant for ART programmes, such as those in Malawi, where renal function is not routinely assessed.

Immune evasion cluster-positive bacteriophages are highly prevalent among human Staphylococcus aureus strains, but they are not essential in the first stages of nasal colonization.

The Staphylococcus aureus immune evasion cluster (IEC), located on ß-haemolysin-converting bacteriophages (ßC-Φs), 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 ßC-Φs in human strains suggested a role for these ßC-Φs 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 ßC-Φ13. Intranasal survival was monitored for 28 days after inoculation. The strain harbouring ßC-Φ13 was eliminated significantly faster (median 4 days; range 1-14 days) than the strain without ßC-Φ13 (median 14 days; range 2-28 days; p 0.011). In conclusion, although IEC-carrying ßC-Φs are highly prevalent among human colonizing S. aureus strains, they are not essential in the first stages of S. aureus nasal colonization.

Application of modern microbiological diagnostic methods for tuberculosis in Macha, Zambia.

SETTING: Macha, Zambia. OBJECTIVE: To assess the benefits of auramine-O staining fluorescence microscopy and Mycobacterial Growth Indicator Tube (MGIT) liquid culture with molecular identification in tuberculosis (TB) diagnostics. DESIGN: One hundred patients suspected of TB were subjected to three sputum sample examinations applying Ziehl-Neelsen (ZN) and auramine-O staining and MGIT culture. Positive cultures were identified using the GenoType CM assay; cultures identified as Mycobacterium tuberculosis complex were the gold standard for a diagnosis of TB. RESULTS: The 100 patients produced 271 sputum samples; of these, 30 patients had positive cultures. M. tuberculosis complex bacilli were isolated in 17 (56.7%) patients, non-tuberculous mycobacteria (NTM) in 11 (36.7%) and other acid-fast bacilli in two. Forty-eight samples (17.7%) were contaminated. Auramine-O detected 16 (57.1%) patients culture-positive for mycobacteria and 12 patients with culture-proven TB, vs. respectively 8 (28.6%, P = 0.008) and 7 (41.2%, P = 0.044) for ZN. Three of eight auramine-positive/ZN-negative patients were culture-positive for NTM only. CONCLUSION: The auramine-O method significantly increases sensitivity, although the higher NTM detection rate implies that this does not in itself lead to a more accurate diagnosis of TB. MGIT culture is highly sensitive, although contamination rates were a drawback; the high frequency of NTM isolation warrants a robust identification method.

Successful treatment for carriage of methicillin-resistant Staphylococcus aureus and importance of follow-up.

With this prospective observational follow-up study of 165 methicillin-resistant Staphylococcus aureus (MRSA)-positive individuals (23 health care workers and 142 patients), we determined that our MRSA eradication therapy protocol results in a high success rate (81%). Five or more negative culture sets give a predictive value for MRSA eradication therapy success of >90%. Furthermore, MRSA colonization, at least in the throat, and the presence of wounds just before the start of MRSA eradication therapy are associated with MRSA eradication therapy failure.

Histoplasma-associated inflammatory pseudotumour of the kidney mimicking renal carcinoma.

A 56-year-old female, originally from Suriname, with an otherwise unremarkable previous medical history was found to have a renal mass highly suspicious for renal cancer for which a nephrectomy was performed. Within the kidney, a tumourous mass was found which, on histological examination, showed an inflammatory pseudotumour caused by Histoplasma capsulatum. Further investigations revealed an idiopathic CD4(+) lymphopenia. Mass lesions mimicking a malignant tumour caused by infection with Histoplasma have rarely been described. To the best of our knowledge, this is the first report of a Histoplasma-associated inflammatory pseudotumour mimicking cancer occurring in the kidney.

[Optimisation of the antibiotic policy in the Netherlands. XII. The SWAB guideline for antimicrobial eradication of MRSA in carriers]. / Optimaliseren van het antibioticabeleid in Nederland. XII. SWAB-richtlijn voor de behandeling van MRSA-dragerschap.

The 'Stichting Werkgroep Antibioticabeleid' (SWAB; Dutch Working Party on Antibiotics Policy) has developed evidence-based guidelines for the antimicrobial treatment of methicillin-resistant Staphylococcus aureus (MRSA) carriers for the eradication of MRSA. A distinction was made between uncomplicated and complicated carriage depending on the presence or absence of an active MRSA infection, skin lesions, foreign body material, mupirocin resistance and/or extranasal carriage. The indication for treatment is determined by the consequences of carriage for the carrier and his/her environment, the adverse events of treatment, and the likelihood of a successful treatment. The first choice of treatment in uncomplicated carriers is a combination of mupirocin nasal ointment and disinfectant soap for 5 days, along with hygiene advice. If treatment fails, sources in the vicinity of the patient must be sought. Complicated carriers receive a combination of 2 oral antibiotics, in addition to mupirocin nasal ointment and disinfectant soap, for at least 7 days.

Aggressiveness and quantification of epithelial proliferation of middle ear cholesteatoma by MIB1.

OBJECTIVE: To assess an easy method that predicts cholesteatoma aggressiveness. STUDY DESIGN: An experimental prospective study. METHODS: Monoclonal antibody MIB1 was used to determine epithelium proliferation in 91 cholesteatomatous ears. Clinical and surgical parameters were compared with proliferation activity to determine pathological and clinical correlation. RESULTS: Statistical correlations were established between hyperproliferation of the cholesteatoma and severe bone erosion (leading to major cholesteatoma complications) and between hyperproliferation and middle ear inflammation (associated with more surgical difficulties and a higher risk of recurrence). A high proliferation index was also found in children's cholesteatoma, which is known to have more aggressive behavior. CONCLUSION: Immunohistochemical use of the MIB1 antibody is a simple technique that can help to determine the aggressiveness of a cholesteatoma.

Characterisation and treatment of roads covered with zinc ashes, muffle furnace fragments and lead slags from former non-ferrous metal industries in Belgium.

Zinc ashes, muffle furnace fragments and lead slags from non-ferrous industries were applied to pave roads in the North of Belgium. From an inventory it appeared that there are at least 490 km of such roads. In our survey the materials on these roads were characterised. The total metal concentration, the availability and the leaching as a function of time were determined. It appeared that these materials contain high concentrations of heavy metals, some of which are readily available. The high leaching of some metals makes them as such unsuitable as secondary construction material. Methods for the application of these materials for road construction were examined where the materials replaced part of the sand and gravel fraction in lean concrete and in bituminous mixtures, or where they replaced the sand in sand-cement mixtures, all these to be used for road foundations, cycle tracks, etc. When lead slags were applied in lean concrete, a material was obtained complying with the standards for secondary construction materials and with sufficient compressive strength for road foundations. When zinc ashes or muffle fragments were used to replace sand in sand-cement mixtures, again a suitable construction material was obtained. The other combinations tried out were rather unsuccessful, because of high metal leaching and/or poor compressive strength.

Determinants of Staphylococcus aureus nasal carriage.

This article aims to review what is currently known of the host and bacterial factors determining S. aureus nasal carriage, including recent developments and future prospects.

Health risk assessment of dioxin emissions from municipal waste incinerators: the Neerlandquarter (Wilrijk, Belgium).

Two municipal waste incinerators in the vicinity of a residential area close to the city of Antwerp caused concern to local habitants. Risk assessment was performed combining chemical, toxicological measurements and model calculations. As the first step in risk assessment an inventory was made of historic emissions from both incinerators with emphasis on dioxins. The operational atmospheric transport and deposition model for priority substances (OPS) was used to calculate the deposition of dioxins in the vicinity of incinerators. The observed soil contamination pattern did not correspond to the calculated deposition pattern, indicating that other sources may contribute at least partly to the local PCDD/PCDF contamination of the area. Dioxin exposure of people in the Neerlandquarter as a function of the food consumption behavior was calculated using a mathematical model (VLIER-HUMAAN) combined with transfer factors. According to the results of these calculations, just residing in the impact area does not result in a meaningful risk. Only if locally produced food was consumed (milk, meat and vegetables), exposure in the Neerlandquarter was enhanced compared to the average dioxin exposure estimated for the Flemish population. Exposure in 1997 was below the exposure in 1980. As a consequence of different eating habits and lower bodyweight, children are subjected to significantly higher exposure than adults. Adverse health outcomes from dioxin exposure in the past cannot be excluded. There was no evidence for enhanced exposure to genotoxicants based on a comparison of chromosomal damage to blood cells of children from the study area to those from a control group.

Tinnitus and otosclerosis.

Fifty patients with otosclerosis and tinnitus were studied for the course of the tinnitus after stapes surgery. Tinnitus disappeared in 64% of the cases, improved in 16%, was unchanged in 14%, and worsened in 6%. The reduction in tinnitus was more favorable after a small fenestra stapedotomy than after a partial stapedectomy with removal of the posterior half of the footplate. An unfavorable postoperative course of tinnitus did not appear to be linked to the postoperative audiometric result. In our study the subjective evaluation of pitch and loudness of the tinnitus did not provide significant information regarding its prognosis.

Labyrinthine fistula after cholesteatomatous chronic otitis media.

OBJECTIVES: To report on cases of labyrinthine fistula diagnosed in an ear, nose, and throat department and to study the incidence, location, pre- and postoperative symptoms (hearing loss, tinnitus, vertigo, facial palsy), preoperative diagnostic imaging, and surgical treatment of two types of cholesteatomatous labyrinthine fistulae-the extensive fistula that erodes both the bony and membranous labyrinths and the bone fistula that affects only the bony labyrinth. STUDY DESIGN: Retrospective case review. PATIENTS: Fifty-four patients with cholesteatomatous chronic otitis media with labyrinthine fistulae. SETTING: Tertiary referral center. INTERVENTIONS: Diagnosis and treatment. MAIN OUTCOME MEASURES: Clinical, imaging, and surgical correlation of extensive fistulae and bone fistulae. RESULTS: The incidence of labyrinthine fistulae was 7% in all patients who underwent surgery for chronic otitis media. The bone type (66%) is more common than the extensive type (33%). Compared with bone fistulae, the outcome for extensive fistulae is more severe in terms of hearing loss, vertigo, and facial palsy. In terms of preoperative diagnosis, computed tomography imaging ensured early diagnosis in 89% of extensive cases and in 28% of bone cases. For extensive fistulae, the surgical technique was more radical, requiring an open technique in 66% of cases versus 22% of the bone fistulae cases. The most common location is the lateral semicircular canal (61%). CONCLUSIONS: The breach in the membranous labyrinth is consistent with a more aggressive pathology, causing more severe pre- and postoperative symptoms. Preoperative computed tomography is more sensitive for diagnosing extensive fistulae, which also require a more radical treatment.

Hickman catheter-related infections in neutropenic patients: insertion in the operating theater versus insertion in the radiology suite.

PURPOSE: To determine the influence of microbial air quality during Hickman catheter insertion in the operating theater versus insertion in the radiology suite on the incidence of catheter-related infections (CRIs). PATIENTS AND METHODS: Hemato-oncologic patients with prolonged neutropenia on antimicrobial prophylaxis were entered onto the study. Catheters were inserted by experienced radiologists under sonographic and fluoroscopic guidance. RESULTS: Forty-eight Hickman catheters in 39 patients were inserted (23 in the operating theater, 25 in the radiology suite). CRIs were seen in 16 catheters (33%; six per 1,000 catheter days; eight in each group). Local infections were found in nine catheters (22%; six in the operating theater v three in the radiology suite; not significant [NS]), catheter-related bacteremia was found in 10 (29%; three in the operating theater v seven in the radiology suite; NS). Coagulase-negative staphylococci (CoNS) caused all CRIs. Despite early vancomycin therapy, 11 (69%; four in the operating room group v seven in the radiology suite group; NS) of the catheters with CRIs had to be removed prematurely. At 90 days after insertion, catheter survival was 78% and 60% (NS) for the operating room and radiology suite, respectively. Multivariate analysis showed that neutropenia increased the CRI risk 20-fold (P =.004) and was strongly related to premature catheter removal owing to infection (relative risk = 11.9; P =.009). Neutropenia on the day of insertion was also significantly correlated with CRI (P =.04) and premature catheter removal owing to infection (P =.03). Serial cultures of blood, exit site, and catheter hub did not predict the development of CRI. CONCLUSION: The high incidence of Hickman CRI caused by CoNS was not associated with insertion location (operating theater v radiology suite). Neutropenia, including neutropenia on the day of insertion, was a significant risk factor for CRI and infection-related catheter removal.

Clonal expansion of Staphylococcus epidermidis strains causing Hickman catheter-related infections in a hemato-oncologic department.

The detailed analysis of 411 strains of coagulase-negative staphylococci (CoNS) obtained from 40 neutropenic hemato-oncologic patients (61 Hickman catheter episodes) on intensive chemotherapy is described. By random amplification of polymorphic DNA (RAPD) analysis, a total of 88 different genotypes were detected: 51 in air samples and 30 in skin cultures prior to insertion, 12 in blood cultures after insertion, and only 5 involved in catheter-related infections (CRI). Two RAPD genotypes of Staphylococcus epidermidis predominated, and their prevalence increased during patient hospitalization. At insertion, these clones constituted 11 of 86 (13%) CoNS isolated from air samples and 33 of 75 (44%) CoNS isolated from skin cultures. After insertion, their combined prevalence increased to 33 of 62 (53%) in catheters not associated with CRI and 139 of 188 (74%) in catheters associated with CRI (P = 0.0041). These two predominant S. epidermidis clones gave rise to a very high incidence of CRI (6.0 per 1,000 catheter days) and a very high catheter removal rate for CRI, 70%, despite prompt treatment with vancomycin. A likely source of S. epidermidis strains involved in CRI appeared to be the skin flora in 75% of cases. The validity of these observations was confirmed by pulsed-field gel electrophoresis (PFGE) of SmaI DNA macrorestriction fragments of blood culture CoNS isolates. Again, two predominant CoNS genotypes were found (combined prevalence, 60%). RAPD and PFGE yielded concordant results in 75% of cases. Retrospectively, the same two predominant CoNS clones were also found among blood culture CoNS isolates from the same hematology department in the period 1991 to 1993 (combined prevalence, 42%) but not in the period 1978 to 1982. These observations underscore the pathogenic potential of clonal CoNS types that have successfully and persistently colonized patients in this hemato-oncology department.

Infectious complications of radiologically inserted Hickman catheters in patients with hematologic disorders.

PURPOSE: To assess the incidence of infections and its influence on the survival of radiologically inserted Hickman catheters (HCs) in patients with hematologic disorders and to determine factors associated with premature HC removal. METHODS: Survival and complications of 175 HCs in 115 patients were studied retrospectively. To describe the data the Kaplan-Meier method and the log-rank test were used, using the date of HC removal due to HC-related infection as endpoint. A stratified Cox regression model was used to determine explanatory factors. RESULTS: Seventy (40%) HCs were removed prematurely because of proven or probable HC-related infections. The incidence of infection leading to HC removal was 4. 78 per 1000 catheter-days for proven HC infections. Univariate analysis revealed that acute myeloid leukemia, acute lymphocytic leukemia, or treatment for these diseases, gender, each subsequent catheter in the same patient and insertion site increased the risk of premature removal of the catheter due to infection. CONCLUSION: Infection is a major problem in patients with HCs. Unfortunately, the factors associated with increased infection rates that were found in this study cannot be influenced. Further studies are necessary to determine the role of environmental conditions in a radiology suite in relation to the risk of developing a catheter-related infection.

Early calcific stenosis of the aortic sorin pericarbon valve implanted in the elderly.

BACKGROUND: We reviewed our experience with the Sorin Pericarbon (Sorin, Saluggia, Italy) valve implanted in the aortic position. METHODS: From January 1990 to January 1996, 143 consecutive patients had a Pericarbon valve implanted in the aortic position. The mean age was 75+/-5 years. Seventy-eight patients (55%) were in New York Heart Association (NYHA) class III or IV. Sixty patients (42%) had one or more concomitant procedures (51 coronary artery bypass grafting [CABG], 7 carotid endarterectomies, 9 others). RESULTS: The hospital mortality rate was 12% (17 of 143 patients). The follow-up was 100% complete and the median time was 42 months (range, 2 to 79 months). There were 36 late deaths, 20 being cardiac-related: 5 non-valve-related, 11 valve-related, and 4 sudden unexpected deaths. The 5-year actuarial survival was 57%+/-5%. There were 6 early valve failures related to a calcific stenosis at a median time of 36 months (range, 5 to 66 months). Three patients had to undergo another operation and one of these patients died. One patient died the day before the planned reoperation and 2 patients are followed with a symptomatic aortic stenosis but refuse reoperation. Freedom from structural deterioration was 93%+/-3% at 4 years. Echocardiographic examination was obtained in 73 patients at a median time of 42 months (range, 4 to 79 months). Four additional asymptomatic patients were found to have calcifications of their prosthesis. The 5-year freedom from thromboembolic events and from endocarditis were, respectively, 87%+/-5% and 92%+/-3%. CONCLUSION: The surprisingly high rate of early failure due to calcific stenosis and of thromboembolic events of the Pericarbon valve implanted in the aortic position in the elderly made us discontinue its use in our institution.