Ceftolozane/tazobactam for the treatment of bacteremia: a systematic literature review (SLR).

BACKGROUND: Bloodstream infections (BSIs), or bacteremia, are responsible for considerable disease burden. Increasing rates of antibiotic resistance and delays in selection of appropriate treatment lead to increased morbidity, mortality, and costs. Due to limitations of current standard treatments, especially for bacteremia caused by resistant pathogens, a systematic literature review (SLR) was conducted to understand the utilization of ceftolozane/tazobactam (C/T) in bacteremia. METHODS: Electronic database searches of EMBASE®, MEDLINE®, CCTR and Northern Lights, as well as hand searches of conference proceedings from the last two annual meetings (i.e., 2018, 2019) of the European Congress of Clinical Microbiological and Infectious Diseases (ECCMID) and the Infectious Diseases Society of America's annual meeting (IDWeek) were conducted. A total of 23 studies reporting on patients with bacteremia receiving C/T were included in the review. RESULTS: Most studies were observational (k = 20 studies), though few interventional studies were also identified (k = 3). Heterogeneity was ubiquitous with respect to source of bacteremia (i.e., primary or secondary), source of infection (for secondary bacteremia), pathogen type, antibiotic resistance, C/T dose, and outcome definitions. This heterogeneity, along with limited data, and small sample sizes (n = 1 to 31) made it difficult to draw any substantial conclusions, though overall results were favorable to C/T with respect to the outcomes of interest. Nineteen studies reported clinical cure or success (primary bacteremia: k = 6, reported range: 33.3% to 100%; secondary bacteremia: k = 8, 60% to 100%; mixed/unspecified bacteremia: k = 10, 50% to 91.7%). Eight studies reported microbiological cure or eradication rates (primary: k = 3, all reporting 100%; secondary: k = 4, 68% to 80%; mixed/unspecified: k = 5, 60% to 80%). Thirteen studies reported mortality (primary: k = 4, 0% to 14%; secondary: k = 7, 0% to 100%; or mixed/unspecified bacteremia: k = 7, 0% to 51.6%). One study each also reported composite clinical response, relapse, hospital re-admission, and hospital length of stay. CONCLUSIONS: Although the available evidence and observed trends for C/T in bacteremia should be interpreted with caution, the direction of effect would support the utilization of C/T for these difficult to treat infections. Future research should supplement the existing evidence by considering the impact of key treatment effect modifiers without contributing to the observed heterogeneity.

Second Blood Meal by Female Lutzomyia longipalpis: Enhancement by Oviposition and Its Effects on Digestion, Longevity, and Leishmania Infection.

Lutzomyia longipalpis is the main vector of visceral leishmaniasis (VL) in America. Physiological and molecular mechanisms of Leishmania infection in sand flies have been studied during the first gonotrophic cycle. There are few studies about these interactions during the second gonotrophic cycle mainly because of the difficulties maintaining sand flies through sequential feeds. Here we standardized conditions to perform the second blood feed efficiently, and our results show that oviposition is an essential factor for the success of multiple feeds. We evaluated the impact of the second blood meal on longevity, protein digestion, trypsin activity, and Leishmania mexicana development within L. longipalpis gut. Mortality of blood-fed females increases after second blood meal as compared to sugar-fed females. Trypsin activity was lower during the second gonotrophic cycle. However, no difference in protein intake was observed between blood meals. There was no difference in the population size of Leishmania in the gut after both blood meals. In this work, we presented an optimized protocol for obtaining sufficient numbers of sand fly females fed on a second blood meal, and we described some physiological and parasitological aspects of the second gonotrophic cycle which might influence the vectorial competence of sand flies.

Evaluation of a temperate climate mosquito, Ochlerotatus detritus (=Aedes detritus), as a potential vector of Japanese encephalitis virus.

The U.K. has not yet experienced a confirmed outbreak of mosquito-borne virus transmission to people or livestock despite numerous autochthonous epizootic and human outbreaks of mosquito-borne diseases on the European mainland. Indeed, whether or not British mosquitoes are competent to transmit arboviruses has not been established. Therefore, the competence of a local (temperate) British mosquito species, Ochlerotatus detritus (=Aedes detritus) (Diptera: Culicidae) for transmission of a member of the genus Flavivirus, Japanese encephalitis virus (JEV) as a model for mosquito-borne virus transmission was assessed. The JEV competence in a laboratory strain of Culex quinquefasciatus (Diptera: Culicidae), a previously incriminated JEV vector, was also evaluated as a positive control. Ochlerotatus detritus adults were reared from field-collected juvenile stages. In oral infection bioassays, adult females developed disseminated infections and were able to transmit virus as determined by the isolation of virus in saliva secretions. When pooled at 7-21 days post-infection, 13% and 25% of O. detritus were able to transmit JEV when held at 23 °C and 28 °C, respectively. Similar results were obtained for C. quinquefasciatus. To our knowledge, this study is the first to demonstrate that a British mosquito species, O. detritus, is a potential vector of an exotic flavivirus.

Composition of Acridid gut bacterial communities as revealed by 16S rRNA gene analysis.

The gut bacterial community from four species of feral locusts and grasshoppers was determined by denaturing gradient gel electrophoresis (DGGE) analysis of bacterial 16S rRNA gene fragments. The study revealed an effect of phase polymorphism on gut bacterial diversity in brown locusts from South Africa. A single bacterial phylotype, consistent with Citrobacter sp. dominated the gut microbiota of two sympatric populations of Moroccan and Italian locusts in Spain. There was evidence for Wollbachia sp. in the meadow grasshopper caught locally in the UK. Sequence analysis of DGGE products did not reveal evidence for unculturable bacteria and homologies suggested that bacterial species were principally Gammaproteobacteria from the family Enterobacteriaceae similar to those recorded previously in laboratory reared locusts.

The gut bacteria of insects: nonpathogenic interactions.

The diversity of the Insecta is reflected in the large and varied microbial communities inhabiting the gut. Studies, particularly with termites and cockroaches, have focused on the nutritional contributions of gut bacteria in insects living on suboptimal diets. The indigenous gut bacteria, however, also play a role in withstanding the colonization of the gut by non-indigenous species including pathogens. Gut bacterial consortia adapt by the transfer of plasmids and transconjugation between bacterial strains, and some insect species provide ideal conditions for bacterial conjugation, which suggests that the gut is a "hot spot" for gene transfer. Genomic analysis provides new avenues for the study of the gut microbial community and will reveal the molecular foundations of the relationships between the insect and its microbiome. In this review the intestinal bacteria is discussed in the context of developing our understanding of symbiotic relationships, of multitrophic interactions between insects and plant or animal host, and in developing new strategies for controlling insect pests.

Eicosanoid involvement in the regulation of behavioral fever in the desert locust, Schistocerca gregaria.

The desert locust Schistocerca gregaria behaviorally thermoregulates in order to try and maintain a favoured "set point" body temperature. Locusts infected with the deuteromycete fungal pathogen Metarhizium anisopliae var acridumchoose a significantly elevated temperature. This "behavioral fever" greatly delays the progress of mycosis. We have confirmed this phenomenon and shown that desert locusts also fever when infected with the bacterial pathogen Serratia marcescens. Elevation in the prefered environmental temperature occurs also upon injection with laminarin and lipopolysaccharide (microbial cell wall components). Since such treatments also stimulate the immune system it would appear that "behavioral fever" is probably a feature of the immune response. The eicosanoid biosynthesis inhibitor dexamethasone prevented laminarin invoked fever. This effect was reversable by arachidonic acid. Therefore in common with the febrile response in mammals behavioral fever in insects may be mediated locally by circulating eicosanoids.

A note: gut bacteria produce components of a locust cohesion pheromone.

AIMS: Faecal pellets from germ-free locusts were used as culture media to determine the ability of locust gut bacteria to synthesize phenolic components of the locust cohesion pheromone. METHODS AND RESULTS: Inoculation of germ-free faecal pellets with Pantoea agglomerans, a species commonly isolated from locusts, resulted in the release of large amounts of guaiacol and small amounts of phenol, both of which are components of the locust cohesion pheromone. Two other locust-derived species, Klebsiella pneumoniae pneumoniae and Enterobacter cloacae, also produced guaiacol from germ-free faecal pellets, but the opportunistic locust pathogen, Serratia marcescens, did not. The most likely precursor for guaiacol is the plant-derived vanillic acid, which is present in large amounts in the faeces of both conventional and germ-free locusts. CONCLUSIONS: These observations are consistent with previous ones, that locust gut bacteria are responsible for the production of components of the locust cohesion pheromone. SIGNIFICANCE AND IMPACT OF THE STUDY: These findings illustrate how an insect can adapt to make use of a common bacterial metabolite produced by one or more of its indigenous gut bacterial species. This observation has implications for our appreciation of insect gut microbiota interactions.

Detection of Leishmania lipophosphoglycan binding proteins in the gut of the sandfly vector.

Binding to the midgut microvillar surface in the sandfly Phlebotomus papatasi is a prerequisite for successful development of Leishmania major within the gut of the vector. This paper describes a method for detecting microvillar-associated proteins which act as ligands for the parasite surface glycoconjugate lipophosphoglycan (LPG). Adhesion of LPG to midgut proteins was visualized by probing midgut extracts with LPG using a Western ligand blotting technique. Procyclic L. major LPG bound to a microvillar polypeptide band of 65 kDa (estimated in the non-reduced state) and bound variably to several lower molecular weight bands, probably degradation products or subunits of the primary binding polypeptides. Specificity of binding was confirmed by co-incubating biotinylated LPG with an LPG-specific mAb which resulted in a great reduction in binding.

Carbohydrate digestion in sandflies: alpha-glucosidase activity in the midgut of Phlebotomus langeroni.

Midgut alpha-glucosidase (EC 3.2.1.20) activities were measured after ingestion of blood and sugar meals by the phlebotomine sandfly Phlebotomus langeroni. alpha-Glucosidase activity increased significantly within 1 hr after a blood meal and was maintained at significantly high activities until 48 hr postfeeding, when it fell to basal activity levels. Midgut alpha-glucosidase activity also increased within 1 hr of feeding on a sucrose meal, but there was no discernable peak in activity during the days postingestion. Differences in the induction of enzyme activity after a sugar meal compared to a blood meal might reflect the mode of ingestion of the two types of meal. The sugar meal is released intermittently into the midgut from the crop, in contrast to the bloodmeal, which is directed into the midgut immediately after ingestion and digested in a "batch" process. Nearly 90% of the alpha-glucosidase activity was associated with midgut cells of sugar fed sandflies compared to only 46% in blood fed insects. Isoelectrofocusing revealed the presence of seven alpha-glucosidases with isoelectric points between 4.3-5.8. No alpha-glucosidase activity was detected in the crop, indicating that glucosidases originate from the midgut epithelium rather than the salivary glands.

Bloodmeal digestion in the midgut of Phlebotomus papatasi and Phlebotomus langeroni.

Bloodmeal digestion in midguts of the sandflies Phlebotomus papatasi and Phlebotomus langeroni (Diptera: Psychodidae) was investigated in optimized assays to detect general protease, trypsin and aminopeptidase activities using synthetic substrates. Optimal activity occurred at pH 8-9 for all enzymes examined in both species. Protease activity peaked at 24-34 h post human bloodmeal in midguts of P. papatasi and 34-48 h in P. langeroni; all endo- and exoprotease activities were completed by 50 h in P. papatasi compared to 72 h in P. langeroni. Hydrolysis of two chymotrypsin substrates was < 2% of trypsin activity in both species. Aminopeptidase activity was associated mainly with the midgut wall, whereas trypsin activity was confined to the midgut lumen. A feature of digestion in P. langeroni was the high level of aminopeptidase recorded within 10 h of the bloodmeal.

Influence of Leishmania infection on blood-meal digestion in the sandflies Phlebotomus papatasi and P. langeroni.

The presence of amastigote-initiated infections of Leishmania major parasites caused a significant suppression in alkaline protease, trypsin and aminopeptidase activity during the first 30 h after ingestion of the infected bloodmeal in Phlebotomus papatasi, the natural vector of L. major. Protease levels were significantly higher in infected flies after 72 h than in the control group, where digestion had ceased. Evidence for the suppression of protease activity in infected P. langeroni, a sympatric but un-natural vector of L. major, was less clear; there was no difference in alkaline protease activity between control and infected groups in the first 24 h. However, protease, trypsin and aminopeptidase activities were elevated after 72 h in infected P. langeroni, indicating a delay in the time to the end of digestion and passage of the bloodmeal. The potential advantages for parasite development in suppressing protease activity and extending the period of bloodmeal digestion are discussed.

Ferroelectric-liquid-crystal/silicon-integrated-circuit spatial light modulator.

We present the design and characterization of a spatial light modulator (SLM) comprising a ferroelectric-liquid-crystal light-modulating layer on top of a silicon integrated circuit. Our SLM consists of two electrically addressed arrays on the same integrated-circuit die. The first, a 1 x 128 linear array with a 20-microm center-to-center element spacing, used shift register addressing, while the second, a 64 x 64 square array with 60-microm pitch, used static random access memory addressing. The resulting SLM could be addressed at frame rates of up to 4.5 kHz and gave singleelement intensity contrast ratios of 12:1.