Impact of transmitted HIV-1 drug resistance on the efficacy of first-line antiretroviral therapy with two nucleos(t)ide reverse transcriptase inhibitors plus an integrase inhibitor or a protease inhibitor.

Objectives: To examine the impact of transmitted drug resistance (TDR) on response to first-line regimens with integrase strand transfer inhibitors (INSTIs) or boosted protease inhibitors (bPIs). Methods: From an Italian observational database (ARCA) we selected HIV-1-infected drug-naive patients starting two NRTIs and either an INSTI or a bPI, with an available pre-ART resistance genotype. The endpoint was virological failure (VF; plasma HIV-1 RNA >200 copies/mL after week 24). WHO surveillance drug resistance mutations and the Stanford algorithm were used to classify patients into three resistance categories: no TDR (A), TDR but fully-active ART prescribed (B), TDR and at least low-level resistance to one or more prescribed drug (C). Results: We included 1365 patients with a median follow-up of 96 weeks (IQR 54-110): 1205 (88.3%) starting bPI and 160 (11.7%) INSTI. Prevalence of TDR was 6.1%, 12.5%, 2.6% and 0% for NRTI, NNRTI, bPI and INSTI, respectively. Cumulative Kaplan-Meier estimates for VF at 48 weeks were 11% (95% CI 10.1%-11.9%) for the bPI group and 7.7% (95% CI 5.4%-10%) for the INSTI group. In the INSTI group, cumulative estimates for VF at 48 weeks were 6% (95% CI 4%-8%) in resistance category A, 5% (95% CI 1%-10%) in B and 50% (95% CI 30%-70%) in C (P < 0.001). Resistance category C [versus A, adjusted hazard ratio (aHR) 12.6, 95% CI 3.2-49.8, P < 0.001] and nadir CD4 (+100 cells/mm3, aHR 0.6, 95% CI 0.4-0.9, P = 0.03) predicted VF. In the bPI group, VF rates were not influenced by baseline resistance. Conclusions: Our data support the need for NRTI resistance genotyping in patients starting an INSTI-based first-line ART.

The influence of different shavers on the skin quantified by non-invasive reflectance confocal microscopy.

BACKGROUND: The impact of personal care devices on skin is mainly assessed using subjective tools. However, new objective, accurate non-invasive in vivo imaging techniques have been developed. The aim of this study was to evaluate the ability of reflectance confocal microscopy (RCM) in quantifying morphological impact of shavers on skin. Furthermore, tape stripping (TS) as method to study morphological impact of shavers was evaluated. METHODS: In 12 healthy male subjects, for two consecutive days, a split-face test was performed in the neck; on one side a shaver was applied, while the other side was exposed to TS. The stratum corneum (SC) thickness was quantified using RCM and sensory observations were evaluated using questionnaires. RESULTS: Shavers with a different impact on skin, can be discriminated by RCM; shaver B removed more SC after application than the skin friendlier shaver A. Furthermore, the changes in SC thickness induced by TS corresponded well to that of the shavers. CONCLUSION: RCM is able to quantify the impact of different shavers on skin. Besides, TS appeared to be a suitable model mimicking the mechanical impact of shavers on skin. RCM in combination with the TS model appeared to be a suitable minimally invasive model to obtain morphological and cell biological data on skin-material interactions caused by different personal care devices.

Listeria meningoencephalitis and anti-GQ1b antibody syndrome.

We report the first case of Listeria monocytogenes meningoencephalitis associated with anti-GQ1b antibody syndrome in an immunocompetent adult. A prompt diagnosis, made thanks to the multidisciplinary contribution, allowed a combined therapeutic approach leading to final favourable outcome, despite several intercurrent complications.

Myocarditis mimicking an acute coronary syndrome: a case related to Salmonella enteritis.

Infective myocarditis is most commonly due to a viral infection; occasionally it has been related to bacteria. Gastrointestinal infections associated with myocarditis have only rarely been described in young people, and the pathogenesis is unclear. We report a case of myocarditis mimicking an acute coronary syndrome (ACS) in a patient hospitalized for fever and diarrhoea. Salmonella enteritidis was isolated from stool, and no other pathogens were found. The coronary angiography was normal, and there were not other coronary artery risk factors, other than hypertension. The patient was treated with ciprofloxacin, acetylsalicylate acid, and ramipril with rapid clinical improvement and normalization of cardiac abnormalities. Final diagnosis of Salmonella enteritis and related myocarditis was made based on clinical, laboratory, ECG and echocardiographical findings.

Impact of hepatitis B vaccination in children born to HBsAg-positive mothers: a 20-year retrospective study.

BACKGROUND: Preventive measures remain the best approach to control the spread of hepatitis B virus (HBV) infection. PATIENTS AND METHODS: To evaluate the effectiveness of vaccination against HBV, we conducted a 20-year retrospective study on 100 subjects, born to hepatitis B surface antigen (HBsAg)-positive mothers, who had received postexposure prophylaxis at the Clinic of Infectious Diseases (Siena University, Italy) during 1984-2004. All patients were tested for the presence of HBsAg, anti-HBs and anti-HB core antigen (anti-HBc). RESULTS: Two subjects (2%) acquired the infection as shown by the presence of anti-HBc. Of the 98 patients who did not acquire the infection, 62 of these (63.3%) had an anti-HBs concentration considered protective (> or =10 mIU/ml). The percentage of protected subjects decreased in relation to time from vaccination with a significant reduction (p = 0.009) of anti-HBs geometric mean titre (GMT) after 5 years, which reached the level of 10 mIU/ml after about 15 years. No patients without protective concentration have acquired the infection as of today. Only 12% of the HBsAg-positive mothers were followed in specialized structures after pregnancy, reflecting the scarce knowledge of the problem in the general population. CONCLUSION: Our data, while confirming the effectiveness of anti hepatitis B vaccination, highlight the need for postvaccination follow-up, particularly in high-risk categories, to prolong protection, through booster doses if necessary. We show, moreover, the importance of maintaining active surveillance in the territory to improve follow-up to chronic carriers and to sensitize families.

Outpatient parenteral antibiotic therapy in the elderly: an Italian observational multicenter study.

Bacterial infections are the most frequent cause of hospitalization in elderly patients. In the early eighties, the advantages of Outpatient parenteral Antibiotic therapy (OPAT) were identified in the United States, and suitable therapeutic programs were established. In order to understand the different ways of managing OPAT, a National OPAT Registry was set up in 2003 in Italy. This study analyzes data concerning bacterial infections in 176 elderly patients including demographics, therapeutic management, clinical response, and side-effects. Bone and joint infections (48.9%) and skin and soft tissue infections (27.8%) were the most common infections treated with OPAT. Teicoplanin (28.9%) and ceftriaxone (22.1%) were the top two antibiotics chosen. OPAT was mainly performed at a hospital infusion center (52.8%). The clinical success rate was high and side-effects were low (12.6% of cases). Management of bacterial infections in the elderly with an outpatient program is effective and safe.

Outpatient parenteral antibiotic therapy for bone and joint infections: an italian multicenter study.

In the early eighties, the advantages of outpatient parenteral antibiotic therapy (OPAT) (reduced costs, no hospitalization trauma in children, no immobilization syndrome in elderly, reduction in nosocomial infections by multiresistant organisms) were identified in the United States, and suitable therapeutic programs were established. Currently, more than 250,000 patients per year are treated according to an OPAT program. In order to understand the different ways of managing OPAT and its results, a National OPAT Registry was set up in 2003 in Italy. Analysis of data concerning osteomyelitis, septic arthritis, prosthetic joint infection and spondylodiskitis, allowed information to be acquired about 239 cases of bone and joint infections, with particular concern to demographics, therapeutic management, clinical response, and possible side effects. Combination therapy was the first-line choice in 66.9% of cases and frequently intravenous antibiotics were combined with oral ones. Teicoplanin (38%) and ceftriaxone (14.7%), whose pharmacokinetic/pharmacodynamic properties permit once-a-day administration, were the two top antibiotics chosen; fluoroquinolones (ciprofloxacin and levofloxacin) were the most frequently utilized oral drugs. Clinical success, as well as patients' and doctors' satisfaction with the OPAT regimen was high. Side-effects were mild and occurred in 11% of cases. These data confirm that the management of bone and joint infections in an outpatient setting is suitable, effective and safe.

Relapsing fever in a traveller from Senegal: determination of Borrelia species using molecular methods.

We describe a case of a febrile patient returning from Senegal in which haemoscopic and molecular investigation confirmed tick-borne relapsing fever (TBRF), suggesting Borrelia crocidurae as the causative agent. This case emphasises the need to include TBRF in the differential diagnosis of fever following a journey from endemic countries, including malarial areas.

[Retrospective study of tuberculosis in the Province of Siena]. / Studio retrospettivo sui ricoveri per tubercolosi nella Provincia di Siena.

We report here the results of a retrospective study carried out on 200 tuberculosis cases admitted to the Hospital of Siena during the period 1994-2003. For each case, epidemiological, clinical and microbiological data were collected in order to analyze the trend of tuberculosis over the years and to compare our experience with similar studies. Indigenous patients were significantly older than immigrants (60.1 vs 34.2 yrs) more frequently affected by underlying chronic diseases. Overcrowding and HIV infection were predisposing conditions in 30 subjects (15% of cases) recently arrived from high endemicity countries. Pulmonary tuberculosis (TB) was diagnosed in 71% of cases, irrespective of origin. The death rate was 5%. Microbiological investigation was positive in 74.4% of examined subjects; 9.8% of isolates were resistant to one or more antituberculous drugs. The number of cases admitted to the Hospital seems to have slowly decreased in the last few years; factors that may influence this trend are discussed. Our results confirm a distinct epidemiological pattern of the disease between indigenous patients and immigrants, which is typical of low-endemicity countries. The delay in the diagnosis and management of the disease observed in this case-series report underlines the need to improve information on TB and skill in treatment, and to maintain specialized centres.

Molecular typing of Staphylococcus aureus isolates from an intensive care unit.

Seventeen S. aureus clinical isolates, collected from an Intensive Care Unit (ICU) during a seven-month period were analyzed to investigate their antimicrobial susceptibility and clonal diversity. Eleven isolates (65%) were found to be resistant to methicillin (MRSA). Pulsed-field gel electrophoresis (PFGE) profiles of genomic DNAs, and analysis of the polymorphisms of the variable regions of the protein A (spa) and coagulase (coa) genes revealed a lower clonal heterogeneity among MRSA than among methicillin-susceptible isolates (MSSA). Two of the MRSA clones were repeatedly isolated in different patients, within a variable period of time, suggesting the presence in the ward of a resident, endemic and multi-drug resistant MRSA population. Our results also emphasize the lower discriminatory power of spa and coa typing compared with PFGE typing.

Staphylococcus aureus nasal carriage in the community: a survey from central Italy.

Recently, concern has increased regarding the spread of methicillin-resistant Staphylococcus aureus (MRSA) in the community. We studied 812 subjects from central Italy to establish the rates of nasal carriage of S. aureus, and antibiotic susceptibility patterns, in the community. The prevalence of S. aureus nasal carriage was 30.5%. Only one subject, with predisposing risk factors for acquisition, was identified as carrier of MRSA (prevalence of 0.12%). The presence of MRSA in the community of our area still appears to be a rare event. Among methicillin-susceptible S. aureus (MSSA) isolates, a surprisingly high rate (18%) of resistance to rifampin was observed.

Muscular-skeletal cryptococcosis in a patient with idiopathic CD4+ lymphopenia.

A healthy 27-year-old woman presented, four months after childbirth, ingravescent pain and claudication of the left lower limb. Magnetic Resonance Imaging of the lumbosacral and iliac regions showed widespread muscular-skeletal lesions. The patient underwent surgery; Cryptococcus neoformans was isolated from surgical samples. Liposomal amphotericin B, fluconazole and itraconazole were administered. Laboratory findings showed lymphocytopenia, with reduction of CD4+ lymphocytes (23 cells per cubic millimeter) in the absence of HIV infection and any other defined immunodeficiency. This is a rare case of muscular-skeletal cryptococcal infection isolated in a subject affected with idiopathic CD4+ lymphocytopenia.

Paclitaxel as a radiosensitiser: a proposed schedule of administration based on in vitro data and pharmacokinetic calculations.

Paclitaxel is efficacious against many human cancers. Because it blocks cells at the radiosensitive G2-M interface, paclitaxel has been investigated as a radiosensitiser. The results have been equivocal and somewhat contradictory. It is impossible to obtain proper pharmacokinetic calculations, aimed at obtaining maximum cytotoxicity and/or radiosensitisation, without knowing (i) how long the drug must be in contact with the cells, (ii) how long the effect lasts after the drug is removed from the cellular environment, (iii) whether the drug acts as a radiosensitiser even when, like cis-platinum, it is added after the radiation and (iv) what the minimum quantity of drug in the cellular environment is required for both chemotoxicity and radiosensitisation. The present work addresses the above questions. Two radioresistant cell lines of human origin were used, A375 melanoma and S549 lung carcinoma, in a clonogenic assay where only colonies with 50 or more cells were counted. For the irradiation, 6 MV X-rays were used. Any G2-M block was quantified by cell cycle kinetics analysis. From the results, a simulation of pharmacokinetics was conducted to calculate the schedule of administration of paclitaxel most likely to achieve and maintain significant chemotoxocity and radiosensitisation. The minimum concentration of paclitaxel for measurable cytotoxicity was 3 nM for both cell lines, but the drug was more toxic to the A549 cells. The minimum concentration for measurable radiosensitisation was 3 nM for A375 and approximately 0.1 nM for A549, but whereas above 3 nM the radiosensitivity increased in A375, it decreased above 1 nM for A549. A minimum of 18 h incubation with the drug was necessary for measurable effects and the radiosensitising effects were lost soon after its removal. There was no radiosensitisation if paclitaxel was added after the radiation, and, at the minimum effective concentrations, it caused only a minor and transient G2-M block. The pharmacokinetic calculations predict that 15 mg/m2 paclitaxel given as a 1 h infusion 5 days/week for 3 weeks during the radiotherapy should achieve both cytotoxicity and radiosensitisation. The mechanism of radiosensitisation by paclitaxel at the concentrations suggested by our results does not appear to be via a G2-M block and is probably concentration dependent. The results imply that low-dose, daily infusions of paclitaxel for as long as possible during a course of radiotherapy are more likely to result in radiosensitisation and prolonged cytotoxicity than high-dose infusions given once a week.

Variations in tumor levels of cis-platinum through a course of fractionated radiotherapy in patients with non-small cell lung cancer.

AIMS AND BACKGROUND: Radiation has been shown to affect the uptake of micromolecules by the tissues within the radiation fields. We measured tumor drug uptake throughout a course of radiotherapy for stage III non-operable non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Thirty patients were treated with radiotherapy consisting of 15 fractions of 300 cGy given over 3 weeks. They were divided into groups of 2. At 1.5 hr before a given fraction of radiotherapy, one group was given i.v. a bolus of 6 mg/m2 CDDP (cis-diamminedichloroplatinum). Between 1.5 and 2 hr after radiotherapy, the patients underwent bronchoscopy, during which a biopsy was taken from the tumor mass. A similar procedure was carried out on a different group of 2 patients at each of the 15 radiotherapy fractions. The amount of platinum in the biopsy sample was measured by atomic absorption spectroscopy and expressed as ng platinum/mg tissue. In another 13 patients, a biopsy was taken before beginning the radiotherapy, and they served as controls. RESULTS: The quantity of platinum/g of tissue in the patients was 11 +/- 4.4 ng/mg tissue. During the course of fractionated radiotherapy, the quantity of platinum/g of tumor varied considerably between radiotherapy fractions. Maximum uptake was at fractions 8 and 9 (92 ng platinum/mg tissue) with the minima during the first few fractions and at fractions 10, 11 and 12 (an average 20 ng platinum/mg tissue). CONCLUSIONS: The cyclical variations in the uptake of CDDP by the tumor tissue during the protracted course of fractionated radiotherapy are probably due to the well-known effects of radiation on vascular function and capillary permeability. The results may have implications for future clinical protocols involving chemo- and radiotherapy for the treatment of the disease.