Interventions in the management of infection in the foot in diabetes: a systematic review.

The expert panel on diabetic foot infection (DFI) of the International Working Group on the Diabetic Foot conducted a systematic review seeking all published reports relating to any type of treatment for infection of the foot in persons with diabetes published as of 30 June 2014. This review, conducted with both PubMed and EMBASE, was used to update an earlier one undertaken on 30 June 2010 using the same search string. Eligible publications included those that had outcome measures reported for both a treated and a control population that were managed either at the same time, or as part of a before-and-after case design. We did not include studies that contained only information related to definition or diagnosis, but not treatment, of DFI. The current search identified just seven new articles meeting our criteria that were published since the 33 identified with the previous search, making a total of 40 articles from the world literature. The identified articles included 37 randomised controlled trials (RCTs) and three cohort studies with concurrent controls, and included studies on the use of surgical procedures, topical antiseptics, negative pressure wound therapy and hyperbaric oxygen. Among the studies were 15 RCTs that compared outcomes of treatment with new antibiotic preparations compared with a conventional therapy in the management of skin and soft tissue infection. In addition, 10 RCTs and 1 cohort study compared different treatments for osteomyelitis in the diabetic foot. Results of comparisons of different antibiotic regimens generally demonstrated that newly introduced antibiotic regimens appeared to be as effective as conventional therapy (and also more cost-effective in one study), but one study failed to demonstrate non-inferiority of a new antibiotic compared with that of a standard agent. Overall, the available literature was both limited in both the number of studies and the quality of their design. Thus, our systematic review revealed little evidence upon which to make recommendations for treatment of DFIs. There is a great need for further well-designed trials that will provide robust data upon which to make decisions about the most appropriate treatment of both skin and soft tissue infection and osteomyelitis in diabetic patients.

Molecular epidemiology of vancomycin-resistant enterococcal bacteraemia: results from the Canadian Nosocomial Infection Surveillance Program, 1999-2009.

OBJECTIVES: Vancomycin-resistant enterococci (VRE) can be associated with serious bacteraemia. The focus of this study was to characterize the molecular epidemiology of VRE from bacteraemia cases that were isolated from 1999 to 2009 as part of Canadian Nosocomial Infection Surveillance Program (CNISP) surveillance activities. METHODS: From 1999 to 2009, enterococci were collected from across Canada in accordance with the CNISP VRE surveillance protocol. MICs were determined using broth microdilution. PCR was used to identify vanA, B, C, D, E, G and L genes. Genetic relatedness was examined using multilocus sequence typing (MLST). RESULTS: A total of 128 cases of bacteraemia were reported to CNISP from 1999 to 2009. In 2007, a significant increase in bacteraemia rates was observed in western and central Canada. Eighty-one of the 128 bacteraemia isolates were received for further characterization and were identified as Enterococcus faecium. The majority of isolates were from western Canada (60.5%), followed by central (37.0%) and eastern (2.5%) Canada. Susceptibilities were as follows: daptomycin, linezolid, tigecycline and chloramphenicol, 100%; quinupristin/dalfopristin, 96.3%; high-level gentamicin, 71.6%; tetracycline, 50.6%; high-level streptomycin, 44.4%; rifampicin, 21.0%; nitrofurantoin, 11.1%; clindamycin, 8.6%; ciprofloxacin, levofloxacin and moxifloxacin, 1.2%; and ampicillin, 0.0%. vanA contributed to vancomycin resistance in 90.1% of isolates and vanB in 9.9%. A total of 17 sequence types (STs) were observed. Beginning in 2006 there was a shift in ST from ST16, ST17, ST154 and ST80 to ST18, ST412, ST203 and ST584. CONCLUSIONS: The increase in bacteraemia observed since 2007 in western and central Canada appears to coincide with the shift of MLST STs. All VRE isolates remained susceptible to daptomycin, linezolid, chloramphenicol and tigecycline.

A systematic review of the effectiveness of interventions in the management of infection in the diabetic foot.

The International Working Group on the Diabetic Foot expert panel on infection conducted a systematic review of the published evidence relating to treatment of foot infection in diabetes. Our search of the literature published prior to August 2010 identified 7517 articles, 29 of which fulfilled predefined criteria for detailed data extraction. Four additional eligible papers were identified from other sources. Of the total of 33 studies, 29 were randomized controlled trials, and four were cohort studies. Among 12 studies comparing different antibiotic regimens in the management of skin and soft-tissue infection, none reported a better response with any particular regimen. Of seven studies that compared antibiotic regimens in patients with infection involving both soft tissue and bone, one reported a better clinical outcome in those treated with cefoxitin compared with ampicillin/sulbactam, but the others reported no differences between treatment regimens. In two health economic analyses, there was a small saving using one regimen versus another. No published data support the superiority of any particular route of delivery of systemic antibiotics or clarify the optimal duration of antibiotic therapy in either soft-tissue infection or osteomyelitis. In one non-randomized cohort study, the outcome of treatment of osteomyelitis was better when the antibiotic choice was based on culture of bone specimens as opposed to wound swabs, but this study was not randomized, and the results may have been affected by confounding factors. Results from two studies suggested that early surgical intervention was associated with a significant reduction in major amputation, but the methodological quality of both was low. In two studies, the use of superoxidized water was associated with a better outcome than soap or povidone iodine, but both had a high risk of bias. Studies using granulocyte-colony stimulating factor reported mixed results. There was no improvement in infection outcomes associated with hyperbaric oxygen therapy. No benefit has been reported with any other intervention, and, overall, there are currently no trial data to justify the adoption of any particular therapeutic approach in diabetic patients with infection of either soft tissue or bone of the foot.

Expert opinion on the management of infections in the diabetic foot.

This update of the International Working Group on the Diabetic Foot incorporates some information from a related review of diabetic foot osteomyelitis (DFO) and a systematic review of the management of infection of the diabetic foot. The pathophysiology of these infections is now well understood, and there is a validated system for classifying the severity of infections based on their clinical findings. Diagnosing osteomyelitis remains difficult, but several recent publications have clarified the role of clinical, laboratory and imaging tests. Magnetic resonance imaging has emerged as the most accurate means of diagnosing bone infection, but bone biopsy for culture and histopathology remains the criterion standard. Determining the organisms responsible for a diabetic foot infection via culture of appropriately collected tissue specimens enables clinicians to make optimal antibiotic choices based on culture and sensitivity results. In addition to culture-directed antibiotic therapy, most infections require some surgical intervention, ranging from minor debridement to major resection, amputation or revascularization. Clinicians must also provide proper wound care to ensure healing of the wound. Various adjunctive therapies may benefit some patients, but the data supporting them are weak. If properly treated, most diabetic foot infections can be cured. Providers practising in developing countries, and their patients, face especially challenging situations.

Preparation and characterization of antibody to galactosyl(alpha 1 leads to 4)galactosyl(beta 1 leads to 4)glucosylceramide.

Antiserum against galactosyl(alpha 1 leads to 4)galactosyl(beta 1 leads to 4)glucosylceramide (globotriaosylceramide, Gb3) was raised in rabbits by the administration of four weekly intramuscular injections of 1.5 mg of the purified glycoplipid along with bovine serum albumin and Freund's complete adjuvant. AntiGb3 activity was quantitated initially by immunoprescipitation employing Gb3 mixed with 100-fold excess of lecithin and cholesterol (1 : 1 or 1 : 2, by wt.) as antigen. Subsequently, complement fixation tests done with antigen preparations containing Gb3/lecithin/cholesterol (1 :6 :20, by wt.) showed antiGb3 titres of up to 1 : 8192. Fractionation of the antiserum by BioGel A5m chromatography indicated the antibody was an IgM immunoglobulin. The partially purified antibody stimulated complement-dependent release of glucose from glucose-containing liposomes prepared with shingomyelin/cholesterol/dicetylphosphate/Gb3 (molar ratio, 100 : 75 :11 :1). The antibody crossreacted with the trisaccharide, Gal(alpha1 leads to 4)Gal(beta1 leads to 4)Glc, but not with galactosylerceramide, lactosylceramide, GM1 ganglioside, globotetraosylceramide, digalactosyldiglyceride or a number of low molecular weight saccharides.

Powassan virus encephalitis resembling herpes simplex encephalitis.

A boy from New York traveling in Nova Scotia had olfactory hallucinations and other signs of temporal lobe involvement, leading to a diagnosis of herpes simplex encephalitis. The patient was treated with vidarabine and made a complete recovery. However, hemagglutination inhibition, complement fixation, and neutralization tests identified Powassan virus (POW) as the pathogen. Shortly before his trip to Nova Scotia, the patient had traveled in an area where POW encephalitis had occurred in humans (the eastern part of the state of New York), and he also came in contact with a known reservoir of POW infection (a groundhog) at home.

Emergence of papovavirus in long-term cultures of astrocytes from progressive multifocal leukoencephalopathy patients.

Primary and secondary cell cultures of brain tissue from two fatal cases of progressive multifocal leukoencephalopathy (PML) were closely monitored by light and electron microscopy and immunochemical labelling for glial fibrillary acidic protein. Although the cell cultures appeared heterogeneous and sometimes included fibroblasts, most of the cells were glial and many were identified as astrocytes by their morphology and immunochemical label. In long-term primary cultures four to four and a half months old and subcultures after many passages, focal cytopathic effect was noted in many cells. At the same time, papovavirions appeared in the nuclei of degenerating cells. However, the identity of these cells could not be established. Also, consistently present in the cultures were large atypical and pleomorphic cells that were likewise morphologically and immunochemically identified as astrocytes. Complete formed virions consistent with papovavirus appeared in the nuclei of some of these cells after several cell passages. The emergence of the virus in these cultured astrocytes supports the recently held notion that there may be in PML an abortive, or nonpermissive, papovavirus infection of this cell type which is believed to undergo cell transformation.

Exposure to Toxoplasma gondii and cat ownership in Nova Scotia.

In this survey, 998 children and adolescents between 7 months and 17 years of age who attended a hospital diagnostic center in the city of Halifax, Nova Scotia, for routine evaluation were tested for Toxoplasma gondii antibody. The 5.2% prevalence rate of antibody for children living in the outlying rural areas was significantly higher than the 1.1% rate among the urban children (P = .0006). Seroprevalence increased with age for both rural and urban children. Cat ownership was associated with antibodies to Toxoplasma among rural children but not urban children. Rural children who lived in a house with more than one cat were two times more likely to be infected than children who had one cat and three times more likely to be infected than children with no cats. The geometric mean titer was also significantly higher among the rural children with more than one cat, 1:152, than rural children with one or no cats, 1:63 (P = .02). In light of these findings for children and adolescents, the association of Toxoplasma infection with cat ownership needs to be thoroughly evaluated among pregnant women in rural areas.

Review of macrolides and ketolides: focus on respiratory tract infections.

The first macrolide, erythromycin A, demonstrated broad-spectrum antimicrobial activity and was used primarily for respiratory and skin and soft tissue infections. Newer 14-, 15- and 16-membered ring macrolides such as clarithromycin and the azalide, azithromycin, have been developed to address the limitations of erythromycin. The main structural component of the macrolides is a large lactone ring that varies in size from 12 to 16 atoms. A new group of 14-membered macrolides known as the ketolides have recently been developed which have a 3-keto in place of the L-cladinose moiety. Macrolides reversibly bind to the 23S rRNA and thus, inhibit protein synthesis by blocking elongation. The ketolides have also been reported to bind to 23S rRNA and their mechanism of action is similar to that of macrolides. Macrolide resistance mechanisms include target site alteration, alteration in antibiotic transport and modification of the antibiotic. The macrolides and ketolides exhibit good activity against gram-positive aerobes and some gram-negative aerobes. Ketolides have excellent activity versus macrolide-resistant Streptococcus spp. Including mefA and ermB producing Streptococcus pneumoniae. The newer macrolides, such as azithromycin and clarithromycin, and the ketolides exhibit greater activity against Haemophilus influenzae than erythromycin. The bioavailability of macrolides ranges from 25 to 85%, with corresponding serum concentrations ranging from 0.4 to 12 mg/L and area under the concentration-time curves from 3 to 115 mg/L x h. Half-lives range from short for erythromycin to medium for clarithromycin, roxithromycin and ketolides, to very long for dirithromycin and azithromycin. All of these agents display large volumes of distribution with excellent uptake into respiratory tissues and fluids relative to serum. The majority of the agents are hepatically metabolised and excretion in the urine is limited, with the exception of clarithromycin. Clinical trials involving the macrolides are available for various respiratory infections. In general, macrolides are the preferred treatment for community-acquired pneumonia and alternative treatment for other respiratory infections. These agents are frequently used in patients with penicillin allergies. The macrolides are well-tolerated agents. Macrolides are divided into 3 groups for likely occurrence of drug-drug interactions: group 1 (e.g. erythromycin) are frequently involved, group 2 (e.g. clarithromycin, roxithromycin) are less commonly involved, whereas drug interactions have not been described for group 3 (e.g. azithromycin, dirithromycin). Few pharmacoeconomic studies involving macrolides are presently available. The ketolides are being developed in an attempt to address the increasingly prevalent problems of macrolide-resistant and multiresistant organisms.

Pulmonary illness associated with exposure to Mycobacterium-avium complex in hot tub water. Hypersensitivity pneumonitis or infection?

BACKGROUND: Mycobacterium avium complex is common in water. When aerosolized, it is frequently inhaled but rarely causes illness in healthy people. Hypersensitivity pneumonitis to inhaled aerosols has been described; these aerosols are from several sources of water. The pneumonitis forms are collectively known as humidifier lung; the responsible agent in the water remains uncertain. PURPOSE: To report five cases of respiratory illness in healthy subjects using hot tubs contaminated with M avium complex. DESIGN: Descriptive case reports. SETTING: Consultations in two teaching hospitals. PATIENTS: Five healthy people developed respiratory illnesses characterized by bronchitis, fever, and "flu-like" symptoms after using a hot tub. Acute exacerbations of their illness developed within hours of heavy use of the hot tubs. INVESTIGATIONS: A chest radiograph and sputum culture in all, BAL in one, CT scan and lung biopsy in another were performed. Culture of the water of the two hot tubs also was done. RESULTS: Chest radiographs showed interstitial infiltrates or a miliary nodular pattern. Cultures of all sputum samples, the lung biopsy specimens, lung lavage and water samples were positive for M avium complex. The lung biopsy specimen revealed noncaseating granulomas. All patients recovered with no treatment for M avium complex. CONCLUSION: We conclude that the M avium complex in the water was responsible for the pulmonary illnesses. The symptoms and the results of investigations are more suggestive of a hypersensitivity pneumonitis than of an infection, but no serologic proof of an immunologic reaction to the M avium complex or water was obtained.

Nosocomial pneumonia on general medical and surgical wards in a tertiary-care hospital.

OBJECTIVE: To describe the demographic, clinical, and microbiologic characteristics of patients who develop nosocomial pneumonia on general medical and surgical wards of a tertiary-care hospital. DESIGN: A 1-year, prospective, descriptive study. SETTING: A 1,100-bed, tertiary-care, urban hospital. POPULATION: Patients experiencing nosocomial pneumonia were identified through surveillance on general medical and surgical wards, using a standard case definition. RESULTS: 92 pneumonias in 85 patients on general wards were identified. The mean age of patients was 63 +/- 17 years, 55 patients (65%) were male, and 75 cases of pneumonia (81%) were acquired on surgical wards. Bacteremia was identified in 8 (13%) of 62 episodes, and 48 (52%) grew potential pathogens from respiratory specimens. Twenty-six patients (28%) required transfer to the intensive-care unit (ICU), and 20 (22%) received mechanical ventilation. By multivariate analysis, patients with a thoracic surgical procedure or with Staphylococcus aureus isolated from respiratory secretions were more likely to require ICU admission. The overall mortality rate was 20% (17/85), with a directly associated mortality of 14% (12/85). Patients who died were older, more frequently resided on a medical ward, and had a greater mean number of comorbidities. These patients often were treated nonaggressively and were not considered candidates for ICU admission due to advanced age and poor underlying clinical status. CONCLUSIONS: Although the morbidity of nosocomial pneumonia in this population was high, as evidenced by high rates of transfer to ICU, the directly associated mortality was relatively low. Those requiring ICU admission require further study to identify preventive measures that could decrease the morbidity in this group. Interventions to prevent pneumonia or to improve prognosis may not be feasible for the majority of these patients who die from nosocomial pneumonia.

Methicillin-resistant Staphylococcus aureus in tertiary care institutions on the Canadian prairies 1990-1992.

OBJECTIVE: To review experience with methicillin-resistant Staphylococcus aureus (MRSA) in tertiary acute-care teaching hospitals on the Canadian prairies. DESIGN: Retrospective review for a 36-month period, 1990 through 1992. SETTING: Five tertiary acute-care teaching hospitals in three Canadian prairie provinces. METHODS: MRSA isolates and susceptibility were identified through the clinical microbiology laboratory at each institution. For each patient, data collected included duration of institutional residence prior to isolation, patient ethnic background, age, sex, and antimicrobial susceptibility. Epidemiologic typing of strains used restriction fragment length polymorphism analysis by pulsed-field gel electrophoresis. RESULTS: Two hundred fifty-nine MRSA isolates were identified in 135 patients during the 36 months, with substantial institutional variation in number of isolates. No consistent increase in yearly numbers of isolates was apparent. Patients usually had MRSA identified at admission (62%); only one of five centers had the majority of isolates acquired nosocomially. Patients with MRSA present at admission were more frequently of aboriginal (First Nations) ethnicity (62% compared with 14% of nosocomial; P < 0.001). Pulsed-field gel electrophoresis of 167 isolates from 135 patients revealed 46 different strains with little interprovincial or interinstitutional identity of strains. CONCLUSIONS: MRSA isolated in patients in tertiary care institutions in these three Canadian provinces usually is acquired prior to admission. A disproportionate number of isolates are identified in aboriginal Canadians. Epidemiologic typing was consistent with a polyclonal origin of MRSA in this geographic area.

Regional dissemination and control of epidemic methicillin-resistant Staphylococcus aureus. Manitoba Chapter of CHICA-Canada.

A methicillin-resistant Staphylococcus aureus (MRSA) strain introduced into the largest tertiary-care teaching hospital in Manitoba in 1993 led to a sustained outbreak with secondary outbreaks at one community hospital, two large long-term-care facilities, and nosocomial transmission at a second teaching hospital. Control measures were consistent at each institution and were coordinated on a province-wide basis. MRSA is not currently endemic in any facility in the province.

Association of oral candidiasis with diabetic control.

Factors associated with oral candidiasis in 51 diabetics were examined. The prevalence of oral yeast infection was 49 (n = 25)%. The association with diabetic control, as measured by fasting blood glucose concentration, urinary glucose concentration, and glycosylated haemoglobin, with the presence of yeast was analysed in the 51 diabetic patients. Glycosylated haemoglobin above 12% was strongly associated with oral yeast infection (odds ratio = 13.00) (p less than 0.001), while fasting blood and urinary glucose concentrations were not. The risk of oral candidiasis among diabetics wearing dentures was significantly higher than among dentate diabetics (odds ratio = 4.78). After controlling for the effect of denture wearing, glycosylated haemoglobin greater than 12% remained highly predictive of oral yeast infection, particularly among diabetics without dentures.

Placental infection with Mycoplasma homonis and Ureaplasma urealyticum: clinical correlation.

Placentas from a clinical study group of 446 high-risk pregnancies and 108 normal pregnancies were cultured for Mycoplasma hominis and Ureaplasma urealyticum and examined histologically. Results were compared and correlated with the clinical history. The recovery rate of U urealyticum, but not of M hominis, was significantly higher in the clinical study than in the control group. Isolation of both mycoplasmas was associated with polymorphonuclear leukocyte infiltration of placental membranes, fetal surface, and umbilical cord. Recovery of mycoplasma was significantly higher with prolonged membrane rupture, spontaneous abortion, stillbirth, and early neonatal death. Isolation of U urealyticum, but not of M hominis, was associated with prematurity, lower birth weight, and intrauterine growth retardation.

Seroepidemiology of Coxiella burnetii among wildlife in Nova Scotia.

We used an indirect immunofluorescence assay to determine antibody titers to phase I and phase II Coxiella burnetii antigens in serum samples from a variety of wild animals in Nova Scotia. Forty-nine percent of the hares, 16.5% of the moose, 7.1% of the raccoons, and 1.5% of the white-tailed deer tested had antibodies to phase I antigen. We conclude that there is extensive infection of the hare population by C. burnetii, with lesser degrees of infection of the moose, raccoon, and deer population.

Antibodies to snowshoe hare virus of the California group in the snowshoe hare (Lepus americanus) population of Nova Scotia.

Serological study showed the presence of antibodies to snowshoe hare virus in 6--14% of snowshoe hares (Lepus americanus) samples in Nova Scotia. This report extends the known range of this virus in North America.

Prevalence of Ascaris lumbricoides infection in a small Nova Scotian community.

A survey of Ascaris lumbricoides prevalence was conducted during 1976 and 1977 in a rural community of Nova Scotia. Of 431 individuals tested, 121 (28.1%) were infected. All those infected were under 20 years of age. There was no difference in the rate of infection between households with pigsties and those without. A significantly higher prevalence rate was found in homes where feces were disposed of in the yard and water was obtained from a dug well. In a concurrent random survey taken in the Halifax metropolitan area, none of the 276 individuals tested was infected.

Apparent stability of herpes simplex virus genomes isolated from primary and recurrent infections and dorsal root ganglia in the mouse.

Following natural or experimental primary infection, herpes simplex virus (HSV) becomes latent in sensory ganglia. Reactivation of latent virus may lead to recurrent disease. If HSV DNA remains stable during primary, recurrent and latent infections, that stability would enable us to trace the transmission of HSV from one individual to another. We inoculated mice in the ear pinna with HSV and collected virus at various intervals during primary infection. In mice surviving primary infections, recurrent disease was induced from which virus was isolated. Virus was also recovered from explanted dorsal root ganglia. Virus isolates were characterised by restriction endonuclease digestion and compared with the original inoculate(s). The data indicate that in all cases except two, the isolates from primary and recurrent infections remained identical to the original inoculates.