A model-based approach to designing developmental toxicology experiments using sea urchin embryos.

The key aim of this paper is to suggest a more quantitative approach to designing a dose-response experiment, and more specifically, a concentration-response experiment. The work proposes a departure from the traditional experimental design to determine a dose-response relationship in a developmental toxicology study. It is proposed that a model-based approach to determine a dose-response relationship can provide the most accurate statistical inference for the underlying parameters of interest, which may be estimating one or more model parameters or pre-specified functions of the model parameters, such as lethal dose, at maximal efficiency. When the design criterion or criteria can be determined at the onset, there are demonstrated efficiency gains using a more carefully selected model-based optimal design as opposed to an ad-hoc empirical design. As an illustration, a model-based approach was theoretically used to construct efficient designs for inference in a developmental toxicity study of sea urchin embryos exposed to trimethoprim. This study compares and contrasts the results obtained using model-based optimal designs versus an ad-hoc empirical design.

Recurrent acute otitis media: a survey of current management in England.

OBJECTIVE: Recurrent acute otitis media is common in children. The preferred treatment measures for recurrent acute otitis media have a mixed evidence base. This study sought to assess baseline practice across ENT departments in England. METHODS: A national telephone survey of healthcare staff was conducted. Every ENT centre in England was contacted. A telephone script was used to ask about antibiotic and grommet use and duration in recurrent acute otitis media cases. RESULTS: Ninety-six centres (74 per cent) provided complete information. Recurrent acute otitis media treatment across England by ENT departments varied. The antibiotic first- and second-line prophylaxis offered varies, with trimethoprim used in 33 centres and 29 centres not offering any antibiotics. The timing or choice about when to use grommets also varies, but 87 centres (91 per cent) offer grommet surgery at one stage. CONCLUSION: The treatments received by children in England for recurrent acute otitis media vary by centre; collaborative research in this area is advised.

Paracoccidioidomycosis due to Paracoccidioides brasiliensis S1 associated with acquired immunodeficiency syndrome: A case report / Paracoccidioidomicosis por Paracoccidioides brasiliensis S1 asociado al síndrome de inmunodeficiencia adquirida: A propósito de un caso

BACKGROUND: Paracoccidioidomycosis (PCM) is an endemic disease in Latin America. In immunocompetent hosts, PCM occurs in two main clinical forms: acute and chronic. However, in HIV-infected patients PCM may show up simultaneous manifestations of acute and chronic forms. CASE REPORT: We present the case of a patient diagnosed with HIV who had disseminated skin lesions and generalized lymphadenopathy, as well as respiratory and central nervous system involvement. The PCM diagnosis was confirmed by direct KOH examination, double immunodiffusion and the isolation of the fungus in samples of an abscess in the subcostal region. The isolate was identified as Paracoccidioides brasiliensis S1 by species-specific PCR using primers for protein-coding gene GP43 (exon 2) followed by PCR-RFLP of the alpha-tubulin gene. CONCLUSIONS: There are few data in literature reporting species-specific molecular identification of Paracoccidioides in HIV/PCM patients. Therefore, this case report may contribute to improve the knowledge about this severe disease, its causative cryptic species, and its consequences to patients

ANTECEDENTES: La paracoccidioidomicosis (PCM) es una enfermedad endémica en Latinoamérica. En los pacientes inmunocompetentes, la PCM cursa con dos principales formas: aguda y crónica. Sin embargo, los pacientes infectados por el VIH pueden presentar manifestaciones simultáneas de las dos formas clínicas. CASO CLÍNICO: Se presenta el caso de un paciente VIH-positivo, con lesiones cutáneas diseminadas, linfadenopatía generalizada y afectación del sistema nervioso central y respiratorio. El diagnóstico de PCM se confirmó mediante un examen directo con KOH, doble inmunodifusión y el aislamiento del hongo en cultivo, a partir de muestras de un absceso en la región subcostal. La cepa aislada se identificó como Paracoccidioides brasiliensis S1 mediante PCR especie-específica del gen codificador de la proteína GP43 (exón 2), seguida de PCR-RFLP del gen de la alfa-tubulina. CONCLUSIONES: Existen pocos datos en la literatura que describan la identificación molecular especie-específica de Paracoccidioides en pacientes con VIH/PCM. Por lo tanto, la presentación de este caso clínico puede contribuir a mejorar el conocimiento sobre esta enfermedad grave, la especie críptica implicada y sus consecuencias para los pacientes

Tongue lesion due to Cryptococcus neoformans as the first finding in an HIV-positive patient / Lesión lingual por Cryptococcus neoformans como primer hallazgo clínico en una paciente VIH positiva

BACKGROUND: Cryptococcosis is a severe universally distributed mycosis which mainly affects immunocompromised hosts. This mycosis is caused by yeasts of two species complex of the genus Cryptococcus: Cryptococcus neoformans and Cryptococcus gattii. Meningeal cryptococcosis is the most frequent clinical presentation of this disseminated mycosis. The oral mucosa involvement is extremely unusual. CASE REPORT: We present a case of cryptococcosis with an unusual clinical form. The patient was assisted because she had an ulcerated lesion on the lingual mucosa. Encapsulated yeasts compatible with Cryptococcus were found in microscopic exams of wet preparations from lingual ulcer clinical samples obtained for cytodiagnosis and mycological studies. Cryptococcus neoformans (C. neoformans var. grubii VNI) was isolated in culture. This patient did not know her condition of HIV seropositive before the appearance of the tongue lesion. CONCLUSIONS: The involvement of the oral mucosa is uncommon in this fungal infection, but is important to include it in the differential diagnosis in HIV positive patients

ANTECEDENTES: La criptococosis es una micosis grave de distribución universal que afecta principalmente a los huéspedes inmunodeficientes. Se han definido dos complejos de especies patógenas: Cryptococcus neoformans y Cryptococcus gattii. La meningoencefalitis es la presentación clínica más frecuente de esta micosis sistémica. La afectación de la mucosa oral es extremadamente rara. CASO CLÍNICO: Presentamos el caso de una paciente VIH positiva con una forma clínica inusual de criptococosis. La enferma presentaba una lesión ulcerada en la punta de la lengua. El examen microscópico en fresco de la escarificación y de la biopsia de esta lesión mostraron levaduras capsuladas compatibles con Cryptococcus. Se obtuvo Cryptococcus neoformans (C. neoformans var. grubii VNI) en los cultivos. La paciente conoció su estado inmunológico (infección por VIH) en el contexto de esta enfermedad oportunista. CONCLUSIONES: La afectación de la mucosa oral es poco común en esta infección fúngica, pero es importante incluirla en el diagnóstico diferencial en pacientes VIH positivos

Nocardia kroppenstedtii: a rare pathogen isolated from the spinal vertebral abscess of a patient on long-term immunosuppressive therapy.

OBJECTIVE: Nocardia kroppenstedtii was isolated from the spinal vertebral abscess of a 78-year-old patient presenting with mid-thoracic pain and bilateral lower limb weakness and numbness. The patient was on long-term immunosuppressive therapy with steroids for underlying autoimmune hemolytic anemia. Investigations showed a T5 pathological fracture and vertebra plana with the erosion of the superior and inferior endplates. There was evidence of paraspinal collection from the T4-T6 vertebrae with an extension into the spinal canal. Analysis of Nocardia 16S rRNA (99.9%, 1395/1396 nt) and secA1 gene (99.5%, 429/431 nt) fragments showed the highest sequence similarity with Nocardia kroppenstedtii type strain (DQ157924), and next with Nocardia farcinica (Z36936). The patient was treated with intravenous carbapenem and oral trimethoprim-sulfamethoxazole for four weeks, followed by another six months of oral trimethoprim-sulfamethoxazole. Despite the improvement of neurological deficits, the patient required assistive devices to ambulate at discharge. This study reports the first isolation of N. kroppenstedtii from the spinal vertebral abscess of a patient from Asia. Infections caused by N. kroppenstedtii may be underdiagnosed as the bacterium can be misidentified as N. farcinica in the absence of molecular tests in the clinical laboratory.

Validating an empiric sulfadiazine-trimethoprim dosage regimen for treatment of Escherichia coli and Staphylococcus delphini infections in mink (Neovison vison).

Antimicrobial agents are used extensively off-label in mink, as almost no agents are registered for this animal species. Pharmacokinetic (PK) and pharmacodynamic (PD) data are required to determine antimicrobial dosages specifically targeting mink bacterial pathogens. The aims of this study were to assess, in a PKPD framework, the empirical dosage regimen for a combination of trimethoprim (TMP) and sulfadiazine (SDZ) in mink, and secondarily to produce data for future setting of clinical breakpoints. TMP and SDZ PK parameters were obtained experimentally in 22 minks following IV or oral administration of TMP/SDZ (30 mg/kg, i.e. 5 mg/kg TMP and 25 mg/kg SDZ). fAUC/MIC with a target value of 24 hr was selected as the PKPD index predictive of TMP/SDZ efficacy. Using a modeling approach, PKPD cutoffs for TMP and SDZ were determined as 0.062 and 16 mg/L, respectively. By incorporating an anticipated potentiation effect of SDZ on TMP against Escherichia coli and Staphylococcus delphini, the PKPD cutoff of TMP was revised to 0.312 mg/L, which is above the tentative epidemiological cutoffs (TECOFF) for these species. The current empirical TMP/SDZ dosage regimen (30 mg/kg, PO, once daily) therefore appears adequate for treatment of wild-type E. coli and S. delphini infections in mink.

In Vivo Validation of a Reversible Small Molecule-Based Switch for Synthetic Self-Amplifying mRNA Regulation.

Synthetic mRNA therapeutics have the potential to revolutionize healthcare, as they enable patients to produce therapeutic proteins inside their own bodies. However, convenient methods that allow external control over the timing and magnitude of protein production after in vivo delivery of synthetic mRNA are lacking. In this study, we validate the in vivo utility of a synthetic self-amplifying mRNA (RNA replicon) whose expression can be turned off using a genetic switch that responds to oral administration of trimethoprim (TMP), a US Food and Drug Administration (FDA)-approved small-molecule drug. After intramuscular electroporation, the engineered RNA replicon exhibited dose-dependent and reversible expression of its encoded protein upon TMP administration. The TMP serum level needed for maximal downregulation of protein translation was approximately 45-fold below that used in humans for therapeutic purposes. To demonstrate the therapeutic potential of the technology, we injected mice with a TMP-responsive RNA replicon encoding erythropoietin (EPO) and successfully controlled the timing and magnitude of EPO production as well as changes in hematocrit. This work demonstrates the feasibility of controlling mRNA kinetics in vivo, thereby broadly expanding the clinical versatility of mRNA therapeutics.

Physiologically-Based Pharmacokinetic Modelling of Creatinine-Drug Interactions in the Chronic Kidney Disease Population.

Elevated serum creatinine (SCr ) caused by the inhibition of renal transporter(s) may be misinterpreted as kidney injury. The interpretation is more complicated in patients with chronic kidney disease (CKD) due to altered disposition of creatinine and renal transporter inhibitors. A clinical study was conducted in 17 patients with CKD (estimated glomerular filtration rate 15-59 mL/min/1.73 m2 ); changes in SCr were monitored during trimethoprim treatment (100-200 mg/day), administered to prevent recurrent urinary infection, relative to the baseline level. Additional SCr -interaction data with trimethoprim, cimetidine, and famotidine in patients with CKD were collated from the literature. Our published physiologically-based creatinine model was extended to predict the effect of the CKD on SCr and creatinine-drug interaction. The creatinine-CKD model incorporated age/sex-related differences in creatinine synthesis, CKD-related glomerular filtration deterioration; change in transporter activity either proportional or disproportional to glomerular filtration rate (GFR) decline were explored. Optimized models successfully recovered baseline SCr from 64 patients with CKD (geometric mean fold-error of 1.1). Combined with pharmacokinetic models of inhibitors, the creatinine model was used to simulate transporter-mediated creatinine-drug interactions. Use of inhibitor unbound plasma concentrations resulted in 66% of simulated SCr interaction data within the prediction limits, with cimetidine interaction significantly underestimated. Assuming that transporter activity deteriorates disproportional to GFR decline resulted in higher predicted sensitivity to transporter inhibition in patients with CKD relative to healthy patients, consistent with sparse clinical data. For the first time, this novel modelling approach enables quantitative prediction of SCr in CKD and delineation of the effect of disease and renal transporter inhibition in this patient population.

CombiANT: Antibiotic interaction testing made easy.

Antibiotic combination therapies are important for the efficient treatment of many types of infections, including those caused by antibiotic-resistant pathogens. Combination treatment strategies are typically used under the assumption that synergies are conserved across species and strains, even though recent results show that the combined treatment effect is determined by specific drug-strain interactions that can vary extensively and unpredictably, both between and within bacterial species. To address this problem, we present a new method in which antibiotic synergy is rapidly quantified on a case-by-case basis, allowing for improved combination therapy. The novel CombiANT methodology consists of a 3D-printed agar plate insert that produces defined diffusion landscapes of 3 antibiotics, permitting synergy quantification between all 3 antibiotic pairs with a single test. Automated image analysis yields fractional inhibitory concentration indices (FICis) with high accuracy and precision. A technical validation with 3 major pathogens, Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus, showed equivalent performance to checkerboard methodology, with the advantage of strongly reduced assay complexity and costs for CombiANT. A synergy screening of 10 antibiotic combinations for 12 E. coli urinary tract infection (UTI) clinical isolates illustrates the need for refined combination treatment strategies. For example, combinations of trimethoprim (TMP) + nitrofurantoin (NIT) and TMP + mecillinam (MEC) showed synergy, but only for certain individual isolates, whereas MEC + NIT combinations showed antagonistic interactions across all tested strains. These data suggest that the CombiANT methodology could allow personalized clinical synergy testing and large-scale screening. We anticipate that CombiANT will greatly facilitate clinical and basic research of antibiotic synergy.

Unexpected Cardiomyopathy and Cardiac Dysfunction after Administration of Sulfadiazine-trimethoprim Medicated Diet to ICR mice (Mus musculus).

For many years, the University of Chicago administered sulfamethoxazole-trimethoprim sulfate (SMZ-TMP) oral suspension to select immunocompromised mouse colonies via the drinking water. In 2014, SMZ-TMP oral suspension was placed on back-order and medicated diet with a different sulfonamide, sulfadiazine-trimethoprim (SDZ-TMP) was used as a replacement. Months after this transition, sentinel mice from the same room as one of the remaining immunocompromised colonies on this diet were found dead or appeared sick. Necropsies revealed cardiomegaly, and histology confirmed myocardial fibrosis in the first 4 sentinel mice examined, consistent with cardiomyopathy. Subsequent sequential monitoring of 2 sentinel mice via echocardiography showed their progression toward decreased cardiac function. Investigation of the housing room revealed that the sentinel mice had been accidently placed on SDZ-TMP diet upon entering the colony housing room. This case report describes cardiomyopathy in 6 ICR mice after long term consumption of SDZ-TMP medicated feed.

Síndrome de secreción inadecuada de hormona antidiurética en paciente con linfoma difuso de células grandes B / Syndrome of inappropriate antidiuretic hormone secretion in a patient with diffuse large B-cell lymphoma

No disponible

Pharmacokinetics of Sulfamethoxazole and Trimethoprim During Venovenous Extracorporeal Membrane Oxygenation: A Case Report.

Extracorporeal membrane oxygenation (ECMO) therapy could affect drug concentrations via adsorption onto the oxygenator and/or associated circuit. We describe a case of a 33-year-old man with severe respiratory failure due to Pneumocystis jirovecii infection on a background of recently diagnosed human immunodeficiency virus infection. He required venovenous ECMO therapy for refractory respiratory failure. Intravenous sulfamethoxazole-trimethoprim (100 and 20 mg/kg/day) was administered in a dosing regimen every 6 hours. Pre-oxygenator, post-oxygenator, and arterial blood samples were collected after antibiotic administration and were analyzed for total sulfamethoxazole and trimethoprim concentrations. The peak sulfamethoxazole and trimethoprim concentrations were 122 mg/L and 5.3 mg/L, respectively. The volume of distribution for sulfamethoxazole was 0.37 and 2.30 L/kg for trimethoprim. The clearance for sulfamethoxazole was 0.35 ml/minute/kg and for trimethoprim was 1.64 ml/minute/kg. The pharmacokinetics of sulfamethoxazole and trimethoprim appear not to be affected by ECMO therapy, and dosing adjustment may not be required.

Micro vs. nano: PLGA particles loaded with trimethoprim for instillative treatment of urinary tract infections.

Recurring infections and increasing resistances continue to complicate treatment of urinary tract infections. To investigate alternative treatment options, trimethoprim loaded micro- (D[4;3] of 1-9 µm) and nanoparticles (Z-Avg of 200-400 nm) were prepared from two types of poly(d,l-lactic-co-glycolic acid) (PLGA) for instillative therapy. While PLGA 503H microparticles could not be loaded with more than 2.6% trimethoprim, PLGA 2300 entrapped 22%. When preparing nanoparticles, both types displayed an even higher drug load of up to 29% using PLGA 2300, while PLGA 503H drug load stagnated at 10%. After eight hours, drug release from microparticles amounted to 55% (503H) and 35% (2300) whereas total drug release occurred after 8 (503H) and 9 days (2300). In case of nanoparticles, trimethoprim was liberated much faster with 60% after 2 h and a complete release after 24 h from both polymers. PLGA 2300 seems to be the better choice for entrapment of trimethoprim in microparticles considering the drug load. Both polymers, however, seem to be viable options for nanoparticles. Due to the higher overall drug load, nanoparticles seem to be advantageous over microparticles for instillative therapy, especially when prepared with PLGA 2300.

Gram-negative Bacteremia in Children With Hematologic Malignancies and Following Hematopoietic Stem Cell Transplantation: Epidemiology, Resistance, and Outcome.

Gram-negative rod (GNR) infections adversely affect the outcome of patients with malignancies and following hematopoietic stem cell transplantation (HSCT). This retrospective observational study aimed to describe the epidemiology, outcome, and resistance patterns of GNR bacteremia in children with hematologic malignancies (HM) and after HSCT during the period spanning from 2010 to 2014 in a tertiary children's hospital. A total of 270 children were included in the analysis; 65 (24%) developed 85 episodes of GNR bacteremia; the rate was 36/122 (29.5%) in post-HSCT and 29/178 (16.3%) in HM patients (P<0.05). Overall, 10% of the GNRs were carbapenem resistant. In multivariate analysis, prolonged neutropenia (≥7 d; odds ratio: 19.5, 95% confidence interval: 2.6-148.4) and total hospitalization for a duration of >30 days in the last 3 months (odds ratio: 17.5, 95% confidence interval: 1.4-224.4) were associated with carbapenem-resistant GNR bacteremia. Thirty-day mortality following GNR bacteremia was 0% in HM and 7/52 episodes (13.5%) in HSCT patients (P<0.05). Carbapenem-resistant versus carbapenem-sensitive bacteremia was associated with longer duration of bacteremia (mean: 3.8 vs. 1.7 d), higher risk for intensive care unit hospitalization (44.4% vs. 10.1%), and higher mortality rate (33% vs. 5.8%) (P<0.05). To summarize, GNR bacteremia was frequent, especially in post-HSCT children. Carbapenem resistance adversely affects patients' outcome, increasing morbidity and mortality. Empirical antibiotic therapy must be adjusted to the local resistance patterns.

An external ventricular drainage catheter impregnated with rifampicin, trimethoprim and triclosan, with extended activity against MDR Gram-negative bacteria: an in vitro and in vivo study.

BACKGROUND: External ventricular drainage (EVD) carries a high risk of ventriculitis, increasingly caused by MDR Gram-negative bacteria such as Escherichia coli and Acinetobacter baumannii. Existing antimicrobial EVD catheters are not effective against these, and we have developed a catheter with activity against MDR bacteria and demonstrated the safety of the new formulation for use in the brain. OBJECTIVES: Our aim was to determine the ability of a newly formulated impregnated EVD catheters to withstand challenge with MDR Gram-negative bacteria and to obtain information about its safety for use in the CNS. METHODS: Catheters impregnated with three antimicrobials (rifampicin, trimethoprim and triclosan) were challenged in flow conditions at four weekly timepoints with high doses of MDR bacteria, including MRSA and Acinetobacter, and monitored for bacterial colonization. Catheter segments were also inserted intracerebrally into Wistar rats, which were monitored for clinical and behavioural change, and weight loss. Brains were removed after either 1 week or 4 weeks, and examined for evidence of inflammation and toxicity. RESULTS: Control catheters colonized quickly after the first challenge, while no colonization occurred in the impregnated catheters even after the 4 week challenge. Animals receiving the antimicrobial segments behaved normally and gained weight as expected. Neurohistochemistry revealed only surgical trauma and no evidence of neurotoxicity. CONCLUSIONS: The antimicrobial catheter appears to withstand bacterial challenge for at least 4 weeks, suggesting that it might offer protection against infection with MDR Gram-negative bacteria in patients undergoing EVD. It also appears to be safe for use in the CNS.

Treatment Outcomes of Stenotrophomonas maltophilia Bacteremia in Critically Ill Children: A Multicenter Experience.

OBJECTIVES: Stenotrophomonas maltophilia is a gram-negative opportunistic bacterium that may cause a myriad of clinical diseases in immunocompromised individuals. We aimed to describe the clinical characteristics, risk factors, mortality, and treatment of S. maltophilia bacteremia in critically ill children, a topic on which data are sparse. DESIGN: A multicenter observational retrospective study in which medical charts of critically ill children with S. maltophilia bacteremia were reviewed between 2012 and 2017. SETTING: Data were collected from each of the four largest PICUs nationwide, allocated in tertiary medical centers to which children with complex conditions are referred regularly. PATIENTS: A total of 68 suitable cases of S. maltophilia bacteremia were retrieved and reviewed. MEASUREMENTS AND MAIN RESULTS: The total occurrence rate of S. maltophilia isolation had increased significantly during the study period (r = 0.65; p = 0.02). The crude mortality was 42%, and the attributed mortality was 18%. Significant risk factors for mortality were a longer length of hospital stay prior to infection (33 d in nonsurvivors vs 28 in survivors; p = 0.03), a nosocomial source of infection (p = 0.02), presentation with septic shock (p < 0.001), and treatment with chemotherapy (p = 0.007) or carbapenem antibiotics (p = 0.05) prior to culture retrieval. On multivariate analysis, septic shock (odds ratio, 14.6; 95% CI, 1.45-147.05; p = 0.023) and being treated with chemotherapy prior to infection (odds ratio, 5.2; 95% CI, 1.59-17.19; p = 0.006)] were associated with mortality. The combination of ciprofloxacin, trimethoprim-sulfamethoxazole, and minocycline resulted in the longest survival time (p < 0.01). CONCLUSIONS: The significant attributed mortality associated with S. maltophilia bacteremia in critically ill children calls for an aggressive therapeutic approach. The findings of this investigation favor a combination of trimethoprim-sulfamethoxazole, ciprofloxacin, and minocycline.

Effectiveness of antibiotics versus ibuprofen in relieving symptoms of nosocomial urinary tract infection: A comparative study.

BACKGROUND AND PURPOSE: Antibiotic therapy has been the mainstay of treatment in the management of hospitalized patients with nosocomial urinary tract infection (UTI); however, its use is associated with an increase in resistance and high cost. Ibuprofen showed effectiveness in relieving symptoms of UTI, but its superiority is questionable. The goal of this study was to compare the effectiveness of antibiotics against ibuprofen in relieving symptoms of UTI and to identify factors that affect symptom relief. METHODS: This study was conducted in three public hospitals in Jordan. Patients with nosocomial UTI were assigned to either antibiotics or ibuprofen. Symptoms of UTI were assessed at the time of initiation of treatment and 5 days later. CONCLUSIONS: Antibiotics were more effective in relieving symptoms of UTI than Ibuprofen. Comorbidity and length of hospitalization affected symptom relief during the treatment of UTI. IMPLICATION FOR PRACTICE: Nurse practitioners in the clinical settings can take an active role in helping patients with UTI to achieve relief of symptoms by supporting the use of antibiotics over ibuprofen in symptom resolution.

Pneumocystis jirovecii pneumonia prophylaxis in allogeneic hematopoietic cell transplant recipients: can we always follow the guidelines?

Pneumocystis jirovecii pneumonia (PCP) is a life-threatening disease in allogeneic hematopoietic cell transplantation (HCT) recipients. Trimethoprim-sulfamethoxazole (TMP-SMX) is the preferred prophylaxis but has significant toxicity. We assessed 139 consecutive HCT patients for PCP prophylaxis in our center. According to our procedures, TMP-SMX should be given as first-line prophylaxis from engraftment. In case of intolerance, atovaquone (ATO) or aerosolized pentamidine may be given. Thirteen (9.3%) patients did not receive prophylaxis because they early died. Of the 126 prophylaxed patients, 113 (90%) received TMP-SMX and 13 (10%) received ATO as first-line regimen. However, only 51/113 (45%) patients received TMP-SMX as the sole prophylaxis: 60 patients were switched to ATO because of side effect. There were 18 PCP cases: 3 occurred before engraftment, 7 occurred under ATO, 3 occurred while prophylaxis was pending the resolution of side effects, and 5 occurred after stopping prophylaxis. No cases occurred under TMP-SMX while 7 (9.6%) cases occurred under first-(n = 13) or second (n = 60)-line ATO. There are many concerns about PCP prophylaxis after HCT: patients may develop PCP before engraftment or several months after stopping immunosuppressors, and half of them do not receive TMP-SMX all along the at-risk periods. New prophylactic drugs and strategies should be evaluated.

Myroides odoratimimus urinary tract infection in an immunocompromised patient: an emerging multidrug-resistant micro-organism.

Background: Myroides spp. are common environmental organisms and they can be isolated predominantly in water, soil, food and in sewage treatment plants. In the last two decades, an increasing number of infections such as urinary tract infections and skin and soft tissue infections, caused by these microorganisms has been reported. Selection of appropriate antibiotic therapy to treat the infections caused by Myroides spp. is difficult due to the production of a biofilm and the organism's intrinsic resistance to many antibiotic classes. Case presentation: We report the case of a 69-year-old immunocompromised patient who presented with repeated episodes of macroscopic haematuria, from Northern Italy.A midstream urine sample cultured a Gram negative rod in significant amounts (> 105 colony-forming units (cfu)/mL), which was identified as Myroides odoratimimus. The patient was successfully treated with trimethoprim/sulfamethoxazole after antibiotic susceptibility testing confirmed its activity. Conclusion: This case underlines the emergence of multidrug resistant Myroides spp. which are ubiquitous in the environment and it demands that clinicians should be more mindful about the role played by atypical pathogens, which may harbour or express multidrug resistant characteristics, in immunocompromised patients or where there is a failure of empiric antimicrobial therapy.

A Drug-Tunable Gene Therapy for Broad-Spectrum Protection against Retinal Degeneration.

Retinal degenerations are a large cluster of diseases characterized by the irreversible loss of light-sensitive photoreceptors that impairs the vision of 9.1 million people in the US. An attractive treatment option is to use gene therapy to deliver broad-spectrum neuroprotective factors. However, this approach has had limited clinical translation because of the inability to control transgene expression. To address this problem, we generated an adeno-associated virus vector named RPF2 that was engineered to express domains of leukemia inhibitory factor fused to the destabilization domain of bacterial dihydrofolate reductase. Fusion proteins containing the destabilization domain are degraded in mammalian cells but can be stabilized with the binding of the drug trimethoprim. Our data show that expression levels of RPF2 are tightly regulated by the dose of trimethoprim and can be reversed by trimethoprim withdrawal. We further show that stabilized RPF2 can protect photoreceptors and prevent blindness in treated mice.