The use of extrapolation based on modeling and simulation to support high-dose regimens of ceftaroline fosamil in pediatric patients with complicated skin and soft-tissue infections.

A model-informed drug development approach was used to select ceftaroline fosamil high-dose regimens for pediatric patients with complicated skin and soft-tissue infections caused by Staphylococcus aureus with a ceftaroline minimum inhibitory concentration (MIC) of 2 or 4 mg/L. Steady-state ceftaroline concentrations were simulated using a population pharmacokinetics (PK) model for ceftaroline fosamil and ceftaroline including data from 304 pediatric subjects and 944 adults. Probability of target attainment (PTA) for various simulated pediatric high-dose regimens and renal function categories were calculated based on patients achieving 35% fT>MIC (S. aureus PK/pharmacodynamic target for 2-log10 bacterial killing). For extrapolation of efficacy, simulated exposures and PTA were compared to adults with normal renal function receiving high-dose ceftaroline fosamil (600 mg 2-h infusions every 8 h). For safety, predicted ceftaroline exposures were compared with observed pediatric and adult data. Predicted ceftaroline exposures for the approved pediatric high-dose regimens (12, 10, or 8 mg/kg by 2-h infusions every 8 h for patients aged >2 to <18 years with normal/mild, moderate, or severe renal impairment, respectively; 10 mg/kg by 2-h infusions every 8 h for patients aged ≥2 months to <2 years with normal renal function/mild impairment) were well matched to adults with normal renal function. Median predicted maximum concentration at steady state (Cmax,ss ) and area under the plasma concentration-time curve over 24 h at steady state pediatric to adult ratios were 0.907-1.33 and 0.940-1.41, respectively. PTAs (>99% and ≥81% for MICs of 2 and 4 mg/L, respectively) matched or exceeded the adult predictions. Simulated Cmax,ss values were below the maximum observed data in other indications, including a high-dose pediatric pneumonia trial, which reported no adverse events related to high exposure.

Variation in Proportion of Blood Cultures Obtained for Children With Skin and Soft Tissue Infections.

OBJECTIVES: To identify variation in the proportion of blood cultures obtained for pediatric skin and soft tissue infections (SSTIs) among children's hospitals. METHODS: We conducted a retrospective cohort study using the Pediatric Health Information System database, which we queried for emergency department (ED)-only and hospital encounters between 2012 and 2017 for children aged 2 months to 18 years with diagnosis codes for SSTI. The primary outcome was proportion of SSTI encounters during which blood cultures were obtained. Encounters with and without blood cultures were compared for length of stay, costs, and 30-day ED revisit and readmission rates, adjusted for patient factors and hospital clustering. We also identified encounters with bacteremia using billing codes for septicemia and bacteremia. RESULTS: We identified 239 954 ED-only and 49 291 hospital SSTI encounters among 38 hospitals. Median proportions of ED-only and hospital encounters with blood cultures were 3.2% (range: 1%- 11%) and 51.6% (range: 25%-81%), respectively. Adjusted ED-only encounters with versus without blood culture had higher costs ($1266 vs $460, P < .001), higher ED revisit rates (3.6% vs 2.9%, P < .001), and higher admission rates (2.0% vs 0.9%, P < .001). Hospital encounters with blood culture had longer length of stay (2.3 vs 2.0 days, P < .001), higher costs ($5254 vs $4425, P < .001), and higher readmission rates (0.8% vs 0.7%, P = .027). The overall proportion of encounters with bacteremia was 0.6% for ED-only encounters and 1.0% for hospital encounters. CONCLUSIONS: Despite multiple studies in which low clinical value was demonstrated and current Infectious Diseases Society of America guidelines arguing against the practice, blood cultures were obtained frequently for children hospitalized with SSTIs, with substantial variation across institutions. Few bacteremic encounters were identified.

Added value of inflammatory markers to vital signs to predict mortality in patients suspected of severe infection.

OBJECTIVE: To evaluate the added value of inflammatory markers to vital signs to predict mortality in patients suspected of severe infection. METHODS: This study was conducted at an acute care hospital (471-bed capacity). Consecutive adult patients suspected of severe infection who presented to either ambulatory care or the emergency department from April 2015 to March 2017 were retrospectively evaluated. A prognostic model for predicting 30-day in-hospital mortality based on previously established vital signs (systolic blood pressure, respiratory rate, and mental status) was compared with an extended model that also included four inflammatory markers (C-reactive protein, neutrophil-lymphocyte ratio, mean platelet volume, and red cell distribution width). Measures of interest were model fit, discrimination, and the net percentage of correctly reclassified individuals at the pre-specified threshold of 10% risk. RESULTS: Of the 1015 patients included, 66 (6.5%) died. The extended model including inflammatory markers performed significantly better than the vital sign model (likelihood ratio test: p < 0.001), and the c-index increased from 0.69 (range 0.67-0.70) to 0.76 (range 0.75-0.77) (p = 0.01). All included markers except C-reactive protein showed significant contribution to the model improvement. Among those who died, 9.1% (95% CI -2.8-21.8) were correctly reclassified by the extended model at the 10% threshold. CONCLUSIONS: The inflammatory markers except C-reactive protein showed added predictive value to vital signs. Future studies should focus on developing and validating prediction models for use in individualized predictions including both vital signs and the significant markers.

Protective and pathogenic roles of resident memory T cells in human skin disorders.

The human skin is populated by recirculating T cells and skin-sessile resident memory T cells (TRM). Skin TRM are constructed during immune responses against antigens that the host immune system encounters in the skin. TRM persist in the same sites for a long time and play important protective roles in skin immune responses in collaboration with other skin-composing cells such as dendritic cells and keratinocytes. These TRM with strong effector functions possibly also engender skin inflammatory disorders. Since human skin T cells, especially TRM, are phenotypically distinct from T cells in the blood circulation, T cells residing in the skin should be directly investigated, without presuming from the activities of blood T cells, in order to understand the functional characteristics of skin T cells in skin disorders. This review summarizes the features of human skin TRM and reviews the immunopathological involvement of TRM in human skin disorders such as infectious disease, inflammatory skin disease, and malignant skin tumors.

Optimising the quality and outcomes of treatments for diabetic foot infections.

INTRODUCTION: Infection is the commonest foot complication that arises in people with diabetes and may lead to amputation and even death. The emergence of multidrug resistant bacteria, especially in Gram negative rods, may have a negative impact on the chances of cure in these patients. AREAS COVERED: We searched the Medline and Pubmed databases for studies using the keywords 'diabetic foot infection' and 'diabetic foot osteomyelits' from 1980 to 2016. Expert commentary: Much has been done in the field of diabetic foot infection regarding pathophysiology, diagnosis and treatment. The construction of multidisciplinary teams is probably the most efficient way to improve the patients' outcome. The rational use of antibiotics and surgical skills are essential in these potentially severe infections. Each case of diabetic infection deserves to be discussed in the light of the current guidelines and the local resources. Because of the overal poor outcome of these infections, prevention remains a priority.

Serum insulin-like growth factor-I (IGF-I), IGF-binding protein-3, and growth hormone levels in collodion babies: a case-control study.

AIM: Because growth failure occurs in many collodion babies, we investigated serum growth hormone (GH), insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3) levels in collodion babies admitted to Gevher Nesibe Hospital, Kayseri, Turkey between 1999 and 2006. PATIENTS AND METHOD: The newborns diagnosed clinically as 'collodion baby' were included in the study group (group 1). Because collodion babies are usually born small for gestational age (SGA) and/or premature, a control group (group 2) was formed by selecting the first infant admitted immediately after each study infant who matched for gestational age (+/- 7 days) and birth weight (+/- 100 g). All infants' blood samples were collected within the first 2 h of life for measurements of serum GH, IGFBP-3 and IGF-I levels. RESULTS: Group 1 consisted of 23 collodion babies (13 males and 10 females) with gestational ages ranging from 32 to 42 weeks, and birth weights ranging from 1,300 to 3,600 g. Ten were born premature and 16 were SGA. Serum IGF-I and IGFBP-3 levels were lower but serum GH levels were higher in collodion babies than in controls. Birth weight was positively correlated with serum IGF-I (r = 0.310, p = 0.046) and IGFBP-3 (r = 0.389, p = 0.011) levels. Serum GH level was negatively correlated with birth weight (r = -0.376, p = 0.014), serum IGF-I (r = -0.567, p <0.001) and IGFBP-3 (r = -0.444, p = 0.003). CONCLUSION: Collodion babies had lower serum IGF-I and IGFBP-3 levels but higher serum GH levels than controls in the present case-control study. The underlying mechanism needs to be explored.

High serum hepatocyte growth factor levels in the acute stage of community-acquired infectious diseases.

Acute serum levels of hepatocyte growth factor (HGF) were studied in 6 clinical groups with (i) gastroenteritis, (ii) skin and soft tissue infection, (iii) urinary tract infection, (iv) septicemia, (v) influenza, and (vi) chronic hepatitis C in comparison with a normal control group using an enzyme-linked immunosorbent assay method. We found that serum HGF levels were significantly higher in patients with acute infectious diseases (p < 0.0001) compared to patients with chronic viral hepatitis and healthy controls. Serum HGF and CRP levels were correlated significantly (r=0.65, p < 10(-7)). We conclude that serum HGF levels are elevated in patients with acute infectious diseases.

[Immunological parallels in the use of ultraviolet irradiation of autoblood in patients with suppurative diseases of soft tissue]. / Immunologicheskie paralleli pri primenenii ul'trafioletovogo oblucheniia autokrovi u bol'nykh s gnoinymi zabolevaniiami miagkikh tkanei.

Ultraviolet irradiation of autoblood in patients with suppurative diseases of soft tissues increased the titer of specific antibacterial antibodies and the number of antibody-producing cells (APC), which was the most expressed in cases when the erythrocytes and leukocytes were exposed separately. Study of the count of APC during UV exposure showed it to increase 6-8 h after the procedure.

Abscess-forming neutrophilic dermatosis: report of three cases associated with hemopathies.

BACKGROUND: The development of different types of neutrophilic dermatosis is reported to occur in the course of malignant hemopathies. These concern mainly Sweet's syndrome, pyoderma gangrenosum, erythema elevatum et diutinum and neutrophilic eccrine hidradenitis. OBSERVATIONS: We have recently encountered the cases of 3 patients who presented all with multiple acneiform papules and dome-shaped aseptic abscesses leaving scars. Pus was sterile in all except case 3 in which slight Staphylococcus aureus growth was shown. However, in this patient, only steroids were effective demonstrating that this bacterium was not responsible for the disease. Histopathology disclosed a dense dermal polymorphonuclear neutrophil infiltrate and some mononuclear cells. Two of these patients had myelodysplastic syndromes while one had IgA myeloma. CONCLUSION: Abscess-forming neutrophilic dermatosis seems to be another type of neutrophilic dermatosis associated with hematological malignancies.

[The clinical significance of membrane-destructive processes and their correction in children with suppurative surgical infection]. / Klinicheskoe znachenie membranodestruktivnykh protsessov i ikh korrektsiia u detei s gnoinoi khirurgicheskoi infektsiei.

The results of examination of 101 patients with purulent surgical infection provide evidence of considerable disorders of cell membrane metabolism which correspond to the severity of the disease. Three states of the antioxidant defence system were distinguished: compensated, subcompensated, and decompensated. It is suggested that antioxidant and membrane-stimulating treatment should be applied with consideration for the types of the course followed by the metabolic processes (metabolically latent, lipoperoxidatative, and peroxidative). The clinical effect of the use of antioxidants in 38 patients is shown.

[Sulfhydryl groups and succinate dehydrogenase of blood lymphocytes in patients with inflammatory processes]. / Sul'fgidril'nye gruppy i suktsinatdegidrogenaza limfotsitov krovi u bol'nykh s vospalitel'nymi protsessami.

Patients with pyo-inflammatory processes were found to have a reduced SH-group content and SDH activity of peripheral blood lymphocytes. A clear dependence between the severity and extent of the pyo-inflammatory process and the SH-group and SDH values. Lymphocyte SDH is more sensitive than the SH-groups to the pyo-inflammatory process and responds by reduced activity. Study of SDH activity and SH-group content of lymphocytes in dynamics are sensitive tests for the severity of the pyo-inflammatory process, unspecific reactivity of the organism, and the efficacy of the applied treatment.

[Oxygen pressure of the capillary blood as an objective criterion for predicting the course of the wound process after surgery in patients with diabetes mellitus]. / Napriazhenie kisloroda kapilliarnoi krovi kak ob' ektivnyi kriterii prognozirovaniia techeniia ranevogo protsessa posle operatsii u bol'nykh sakharnym diabetom.

Percutaneous measurement of the capillary blood PO2 was used in 20 normal subjects, 20 patients with diabetes mellitus without purulent pathology, and 34 patients with diabetes mellitus and purulent-inflammatory soft tissues diseases. In patients with diabetes mellitus without purulent pathology, oxygen supply of the skin was reduced by 33%, and in patients with purulent inflammatory diseases--by 55% when compared with that of the normal subjects. After debridement of a purulent wound with drainage and placing the sutures in low PO2 indices at a distance of 1 cm from the wound edge, microcirculation should be restored at day 2-3 after the operation by means of heparin electrophoresis through the perforated drainage tube in the closed wound. This ensures primary healing of 93.8% of the wounds.

Characterization of a soft-tissue infection model in the horse and its response to intravenous cephapirin administration.

A soft-tissue infection model was created in eight horses by infecting subcutaneous tissue chambers with Streptococcus zooepidemicus organisms. Responses of the horses to the infections were determined by monitoring changes in the complete blood count and body temperature and by following changes in the cytology and protein content of the tissue chambers. Systemic reactions to the infections included a mild neutrophilia, mild pyrexia and mild anemia. There was a marked influx of neutrophils and protein into the chambers after they were seeded with bacteria and chamber neutrophil viability decreased markedly at the height of the infection. Subsequent to establishing tissue chamber infections four of the horses were treated with intravenous cephapirin t.d. at a dosage of 20 mg/kg for 5 days. Quantitative culturing of tissue chamber fluid was performed to analyze the efficacy of cephapirin therapy. Cephapirin therapy was accompanied by decreases in the systemic neutrophilia, pyrexia, anemia, and chamber bacterial counts. However, cephapirin did not eliminate the infection in any of the chambers. Chamber neutrophil viability was markedly increased during the cephapirin therapy period.

[Myeloperoxidase deficiency as a cause of recurrent infections]. / Der Myeloperoxidase-Mangel als Ursache rezidivierender Infektionen.

Myeloperoxidase (MPO) deficiency is a common hereditary leukocyte function defect. A two year old girl with MPO-deficiency suffered from recurrent skin infections. No MPO-activity was detectable in leukocytes of her peripheral blood smears, while NBT reduction and chemotactic activity was normal. The quantitative enzyme determination in leukocyte sonicates confirmed the total MPO-deficiency in the girl's leukocytes and a partial MPO-deficiency in the cells of her mother. The patient leukocytes demonstrated also an impaired chemiluminescence.

[Determination of pathogens in blood in disseminated gonococcal infection. Case report and overview of the literature]. / Erregernachweis im Blut bei disseminierter Gonokokkeninfektion. Kasuistik und Literaturübersicht.

Although Neisseria gonorrhoeae has been recognized as causative agent of infectious disease not only of the genital region but also of other organs already at the end of the 19th century, disseminated gonococcal infection as a clinical entity has been defined fairly recently, i.e., during the last decade. In particular, it has been very difficult for a long time to detect Neisseria gonorrhoeae in the blood of patients suffering from this form of gonorrhea. Therefore, the case of a 22-year-old woman is presented who developed fever, arthritis, and pustules and from whose cervix, rectum, and blood Neisseria gonorrhoeae could be grown. Based on the reports in the literature and our own experience indispensable and further desirable diagnostic measures to be adopted in such cases are discussed.

An immunoglobulin (IgG) inhibitor of polymorphonuclear leukocyte motility in a patient with recurrent infection.

We isolated from the serum of a patient with recurrent skin infections an IgG immunoglobulin that irreversibly inhibits the random motility and chemotactic responsiveness of polymorphonuclear leukocytes. Although the patient's leukocytes behaved like normal cells with respect to adherence, phagocytosis, degranulation, and generation of the superoxide anion, they did not migrate normally toward standard chemotactic stimuli. Normal human polymorphonuclear leukocytes behaved similarly after incubation with the patient's serum. Inhibition of motility was not associated with cyutotoxicity. Inhibitory activity could be removed completely from the patient's serum by treatment with either agarose-bound anti-human IgG or Sepharose-bound staphylococcal protein A. Exposure of normal polymorphonuclear leukocytes to as little as 1.25 microgram per milliliter (0.00125 g per liter) of the patient's purified IgG caused significant inhibition of random motility and chemotactic responsiveness (P < 0.01). Thus, IgG immunoglobulins can inhibit leukocyte motility specifically and irreversibly, and thereby adversely affect host defenses against invading microorganisms.

A familial defect of neutrophil chemotaxis with asthma, eczema, and recurrent skin infections.

A defect in chemotaxis of peripheral blood polymorphonuclear leukocytes (PMN's) was demonstrated in both parents and three of four children in a single family afflicted with varying degrees of respiratory allergy, unusual onset of severe eczema in the first month of life, and recurrent bacterial skin infections. Of great interest was the identification of HLA-B12 at the B locus in all affected members but not in the unaffected child. The two children known since infancy to be most severely affected with eczema and recurrent infections are HLA identical and homozygous for HLA-B12. The child without eczema and infections had an intermediate cellular chemotactic defect most apparent on kinetic studies.