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Examination of viability of trypomastigotes before and after single-dose pentamidine treatment demonstrated that single-dose pentamidine substantially affected motility of trypomastigotes, a proxy of drug efficacy. This suggests that single-dose pentamidine may be of added value to bridge time until suramin will be available for treatment of human East Africa trypanosomiasis.

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.

In the COVID-19 era, while we are encouraged to be physically far away from each other, social and scientific networking is needed more than ever. The dire consequences of social distancing can be diminished by social networking. Social media, a quintessential component of social networking, facilitates the dissemination of reliable information and fighting against misinformation by health authorities. Distance learning, telemedicine, and telehealth are among the most prominent applications of networking during this pandemic. Additionally, the COVID-19 pandemic highlights the importance of collaborative scientific efforts. In this chapter, we summarize the advantages of harnessing both social and scientific networking in minimizing the harms of this pandemic. We also discuss the extra collaborative measures we can take in our fight against COVID-19, particularly in the scientific field.

Since the beginning of 2020, the coronavirus disease (COVID-19) pandemic has dramatically influenced almost every aspect of human life. Activities requiring human gatherings have either been postponed, canceled, or held completely virtually. To supplement lack of in-person contact, people have increasingly turned to virtual settings online, advantages of which include increased inclusivity and accessibility and a reduced carbon footprint. However, emerging online technologies cannot fully replace in-person scientific events. In-person meetings are not susceptible to poor Internet connectivity problems, and they provide novel opportunities for socialization, creating new collaborations and sharing ideas. To continue such activities, a hybrid model for scientific events could be a solution offering both in-person and virtual components. While participants can freely choose the mode of their participation, virtual meetings would most benefit those who cannot attend in-person due to the limitations. In-person portions of meetings should be organized with full consideration of prevention and safety strategies, including risk assessment and mitigation, venue and environmental sanitation, participant protection and disease prevention, and promoting the hybrid model. This new way of interaction between scholars can be considered as a part of a resilience system, which was neglected previously and should become a part of routine practice in the scientific community.

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.

Introduction: The association between cardiac autonomic and left ventricular (LV) dysfunction in Chagas disease (ChD) is controversial. Methods: A standardized protocol that includes the Valsalva maneuver, a respiratory sinus arrhythmia (RSA) test, and an echocardiographic examination was used. Spearman correlation coefficients (rho) were used to investigate associations. Results: The study population consisted of 118 ChD patients undergoing current medical treatment, with an average LV ejection fraction of 51.4 +/- 2.6%. The LV ejection fraction and diastolic dimension were correlated with the Valsalva index (rho=0.358, p

Item does not contain fulltext BACKGROUND: Earlier antiretroviral therapy initiation and pre-exposure prophylaxis (PrEP) prevent HIV, although at a substantial cost. We use mathematical modeling to compare the cost-effectiveness and economic affordability of antiretroviral-based prevention strategies in rural Macha, Zambia. METHODS: We compare the epidemiological impact and cost-effectiveness over 40 years of a baseline scenario (treatment initiation at CD4

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].

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.

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.

IntroductionThere is an increased interest in developing once-daily regimens for the treatment of HIV-infected patients. A Phase II study was conducted to investigate the pharmacokinetics, and short-term safety and efficacy of an indinavir/ritonavir combination as part of a once-daily regimen.MethodsHIV-infected patients with either proven poor compliance to HAART regimens in the past or an anticipated poor compliance to such a regimen in the future were eligible for this study. They received a once-daily regimen consisting of indinavir 1200 mg, ritonavir 400 mg, and one or two nucleoside reverse transcriptase inhibitors (NRTIs), also administered once daily with food. A 24 h pharmacokinetic profile was constructed in a subset of patients. Short-term safety and efficacy were evaluated at 4, 12 and 24 weeks after initiation of treatment.ResultsA total of 64 patients were included in this study, of whom 27 (42.2%) were treatment-naive. The geometric mean (+95% CI) of indinavir AUC0–24h, Cmaxand Cminas determined in an unselected group of 16 patients were 84.9 (69.7–103.5) mg/l.h, 12.0 (10.2–14.1) mg/l and 0.15 (0.09–0.26) mg/l, respectively. A large interpatient variability was observed, with five out of the 16 subjects having a Cminvalue below the minimum effective concentration of 0.10 mg/l. During the 24 weeks of follow-up nine patients (14.1%) discontinued study medication, two due to medication-related toxicity. Gastrointestinal adverse events were reported most frequently (50.0%), followed by skin effects (45.3%), joint pain (9.4%) and urological complaints (7.8%). No patient developed nephrolithiasis. The median (+interquartile range) serum creatinine level in the 64 patients increased slightly from 74 (63–88) μmol/l to 79 (66–92) μmol/l during the 24 weeks of follow-up. One new patient reached a grade 1 elevation in serum creatinine, which normalized during the follow-up; five other patients with elevated serum creatinine at baseline remained stable. During the 24 weeks of follow-up, the proportion of patients with a viral load 3in these two sub-groups, respectively.ConclusionThe 24-week follow-up data of this study indicate favourable pharmacokinetics of an indinavir/ritonavir 1200/400 mg combination as part of a once-daily regimen consisting also of one or two NRTIs. Short-term safety and efficacy were also satisfactory. Long-term follow up is planned to evaluate the durability of these results.

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.

Contains fulltext : 118224.pdf (Publisher’s version ) (Open Access) BACKGROUND: Pre-exposure prophylaxis (PrEP) with tenofovir and emtricitabine effectively prevents new HIV infections. The optimal scenario for implementing PrEP where most infections are averted at the lowest cost is unknown. We determined the impact of different PrEP strategies on averting new infections, prevalence, drug resistance and cost-effectiveness in Macha, a rural setting in Zambia. METHODS: A deterministic mathematical model of HIV transmission was constructed using data from the Macha epidemic (antenatal prevalence 7.7%). Antiretroviral therapy is started at CD4

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 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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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

In this issue of Clinical Infectious Diseases Apisarnthanarak et al. tackle an issue that is of major importance to all persons involved in infectious diseases. The message that a relatively simple and inexpensive although laborious intervention program can have a major impact on antibiotic use as well as on antimicrobial resistance should prompt all health care providers (not only those in developing countries!) to put even more effort into controlling antibiotic use and resistance. Antibiotic resistance is on the rise globally and it is mainly driven by the selective pressure imposed by (inappropriate) antibiotic use. Antibiotics are among the most commonly prescribed drugs in hospitals and infections with drug-resistant microorganisms increase the cost of health care length of hospital stay and mortality. Even in a country such as The Netherlands with its low rates of antibiotic use and resistance rates antibiotic use is often not appropriate. The major reason that antibiotics are prescribed inappropriately is that there is a lack of knowledge about infectious diseases and antimicrobial therapy; health care providers are afraid not to prescribe antibiotics. (excerpt)

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.