Detection of Epidemic Scarlet Fever Group A Streptococcus in Australia.

Sentinel hospital surveillance was instituted in Australia to detect the presence of pandemic group A Streptococcus strains causing scarlet fever. Genomic and phylogenetic analyses indicated the presence of an Australian GAS emm12 scarlet fever isolate related to United Kingdom outbreak strains. National surveillance to monitor this pandemic is recommended.

Controlled Infection Immunization Using Delayed Death Drug Treatment Elicits Protective Immune Responses to Blood-Stage Malaria Parasites.

Naturally acquired immunity to malaria is robust and protective against all strains of the same species of Plasmodium This develops as a result of repeated natural infection, taking several years to develop. Evidence suggests that apoptosis of immune lymphocytes due to uncontrolled parasite growth contributes to the slow acquisition of immunity. To hasten and augment the development of natural immunity, we studied controlled infection immunization (CII) using low-dose exposure to different parasite species (Plasmodium chabaudi, P. yoelii, or P. falciparum) in two rodent systems (BALB/c and C57BL/6 mice) and in human volunteers, with drug therapy commencing at the time of initiation of infection. CIIs with infected erythrocytes and in conjunction with doxycycline or azithromycin, which are delayed death drugs targeting the parasite's apicoplast, allowed extended exposure to parasites at low levels. In turn, this induced strong protection against homologous challenge in all immunized mice. We show that P. chabaudi/P. yoelii infection initiated at the commencement of doxycycline therapy leads to cellular or antibody-mediated protective immune responses in mice, with a broad Th1 cytokine response providing the best correlate of protection against homologous and heterologous species of PlasmodiumP. falciparum CII with doxycycline was additionally tested in a pilot clinical study (n = 4) and was found to be well tolerated and immunogenic, with immunological studies primarily detecting increased cell-associated immune responses. Furthermore, we report that a single dose of the longer-acting drug, azithromycin, given to mice (n = 5) as a single subcutaneous treatment at the initiation of infection controlled P. yoelii infection and protected all mice against subsequent challenge.

Discovery of mcr-1-Mediated Colistin Resistance in a Highly Virulent Escherichia coli Lineage.

Resistance to last-line polymyxins mediated by the plasmid-borne mobile colistin resistance gene (mcr-1) represents a new threat to global human health. Here we present the complete genome sequence of an mcr-1-positive multidrug-resistant Escherichia coli strain (MS8345). We show that MS8345 belongs to serotype O2:K1:H4, has a large 241,164-bp IncHI2 plasmid that carries 15 other antibiotic resistance genes (including the extended-spectrum ß-lactamase blaCTX-M-1) and 3 putative multidrug efflux systems, and contains 14 chromosomally encoded antibiotic resistance genes. MS8345 also carries a large ColV-like virulence plasmid that has been associated with E. coli bacteremia. Whole-genome phylogeny revealed that MS8345 clusters within a discrete clade in the sequence type 95 (ST95) lineage, and MS8345 is very closely related to the highly virulent O45:K1:H4 clone associated with neonatal meningitis. Overall, the acquisition of a plasmid carrying resistance to colistin and multiple other antibiotics in this virulent E. coli lineage is concerning and might herald an era where the empirical treatment of ST95 infections becomes increasingly more difficult.IMPORTANCEEscherichia coli ST95 is a globally disseminated clone frequently associated with bloodstream infections and neonatal meningitis. However, the ST95 lineage is defined by low levels of drug resistance amongst clinical isolates, which normally provides for uncomplicated treatment options. Here, we provide the first detailed genomic analysis of an E. coli ST95 isolate that has both high virulence potential and resistance to multiple antibiotics. Using the genome, we predicted its virulence and antibiotic resistance mechanisms, which include resistance to last-line antibiotics mediated by the plasmid-borne mcr-1 gene. Finding an ST95 isolate resistant to nearly all antibiotics that also has a high virulence potential is of major clinical importance and underscores the need to monitor new and emerging trends in antibiotic resistance development in this important global lineage.

Infectivity of Plasmodium falciparum in Malaria-Naive Individuals Is Related to Knob Expression and Cytoadherence of the Parasite.

Plasmodium falciparum is the most virulent human malaria parasite because of its ability to cytoadhere in the microvasculature. Nonhuman primate studies demonstrated relationships among knob expression, cytoadherence, and infectivity. This has not been examined in humans. Cultured clinical-grade P. falciparum parasites (NF54, 7G8, and 3D7B) and ex vivo-derived cell banks were characterized. Knob and knob-associated histidine-rich protein expression, CD36 adhesion, and antibody recognition of parasitized erythrocytes (PEs) were evaluated. Parasites from the cell banks were administered to malaria-naive human volunteers to explore infectivity. For the NF54 and 3D7B cell banks, blood was collected from the study participants for in vitro characterization. All parasites were infective in vivo However, infectivity of NF54 was dramatically reduced. In vitro characterization revealed that unlike other cell bank parasites, NF54 PEs lacked knobs and did not cytoadhere. Recognition of NF54 PEs by immune sera was observed, suggesting P. falciparum erythrocyte membrane protein 1 expression. Subsequent recovery of knob expression and CD36-mediated adhesion were observed in PEs derived from participants infected with NF54. Knobless cell bank parasites have a dramatic reduction in infectivity and the ability to adhere to CD36. Subsequent infection of malaria-naive volunteers restored knob expression and CD36-mediated cytoadherence, thereby showing that the human environment can modulate virulence.

Protein-based profiling of the immune response to uropathogenic Escherichia coli in adult patients immediately following hospital admission for acute cystitis.

Urinary tract infections (UTIs) caused by uropathogenic Escherichia coli (UPEC) are common infections in humans. Despite the substantial healthcare cost represented by these infections, the human immune response associated with the infection immediately following the onset of symptoms in patients remains largely undefined. We performed a prospective study aimed at defining the milieu of urinary cytokines in adult inpatients in the 24-48 h period immediately following hospital admission for acute cystitis due to UPEC. Urine samples, analyzed using 27-target multiplex protein assays, were used to generate immune profiles for patients and compared to age- and gender-matched healthy controls. The levels of multiple pro-inflammatory cytokines were significantly elevated in urine as a result of infection, an observation consistent with prior findings in murine models and clinical literature. We also identified significant responses for several novel factors not previously associated with the human response to UTI, including Interleukin (IL)-4, IL-7, IL-9, IL-17A, eotaxin, Granulocyte-macrophage colony-stimulating factor (GM-CSF) and several growth factors. These data establish crucial parallels between the human immune response to UPEC and murine model UTI studies, and emphasize the complex but poorly defined nature of the human immune response to UPEC, particularly in the immediate period following the onset of symptoms for acute cystitis.

Calcitriol-mediated hypercalcemia: causes and course in 101 patients.

CONTEXT: Hypercalcemia mediated by 1,25-dihydroxy vitamin D (calcitriol) is uncommon, with evidence on etiology limited to small case series or case reports. OBJECTIVE: The objective of the study was to systematically identify a large series of cases of calcitriol-mediated hypercalcemia and document the presentation, demographics, and clinical course across etiologies. DESIGN, SETTING, AND PATIENTS: The study was a hospital-based, retrospective case series, identifying subjects from 1999 through 2009 across the public hospital system in Queensland, Australia. All patients aged over 18 years were identified that had persistent hypercalcemia associated with elevated or inappropriately normal calcitriol concentration or elevated serum angiotensin-converting enzyme. RESULTS: A total of 101 cases were identified. Sarcoidosis was the most common etiology (49%), followed by hematological malignancy (17%) and infections (8%). Etiologies not previously described include squamous cell carcinoma of the tongue, ovarian cystadenocarcinoma, and chronic lymphocytic leukemia. Median serum angiotensin-converting enzyme was higher in sarcoid patients compared with all other causes [218 U/L (176-277) vs 155 U/L (110-208), P < .001], but a level above the normal range did not discriminate well between cases of sarcoidosis and other causes (specificity at cutoff of 130 U/L was only 31%). However, a value greater than 250 U/L was highly specific (89%) for sarcoidosis but lacked sensitivity (31%). A calcitriol level greater than 300 pmol/L was not seen in sarcoidosis but was seen with other etiologies. Cases with neoplastic etiologies were older (61.4 ± 11.4 y) than all other subjects (51.7 ± 15.0 y, P = .006). CONCLUSIONS: Hypercalcemia mediated by calcitriol remains a rare presentation. In almost half the cases, sarcoidosis was the underlying cause, whereas a third of patients had cancer or systemic infections.

Asymptomatic bacteriuria: prevalence rates of causal microorganisms, etiology of infection in different patient populations, and recent advances in molecular detection.

Bacteriuria, or the presence of bacteria in urine, is associated with both asymptomatic and symptomatic urinary tract infection and underpins much of the dynamic of microbial colonization of the urinary tract. The prevalence of bacteriuria in dissimilar patient groups such as healthy adults, institutionalized elderly, pregnant women, and immune-compromised patients varies widely. In addition, assessing the importance of 'significant bacteriuria' in infected individuals represents a diagnostic challenge, partly due to various causal microorganisms, and requires careful consideration of the distinct etiologies of bacteriuria in different populations and circumstances. Recent molecular discoveries have revealed how some bacterial traits can enable organisms to grow in human urine, which, as a fitness adaptation, is likely to influence the progression of bacteriuria in some individuals. In this review, we comprehensively analyze currently available data on the prevalence of causal organisms with a focus on asymptomatic bacteriuria in dissimilar populations. We evaluate recent advances in the molecular detection of bacteriuria from a diagnostic viewpoint and briefly discuss the potential benefits and some of the challenges of these approaches. Overall, this review provides an update on the comparative prevalence and etiology of bacteriuria from both microbiological and clinical perspectives.