Novel techniques in the treatment of skin and soft tissue infection.

PURPOSE OF REVIEW: Global antibiotic resistance is compromising the management of soft tissue infection and Acute Bacterial Skin and Skin Structure Infection (ABSSI). This review describes a novel topical treatment Reactive Oxygen (RO) gel which could compliment and in some situations replace systemic antibiotics. RECENT FINDINGS: A novel topical treatment RO gel could have an important role in treatment, infection prevention and antimicrobial stewardship. RO is highly antimicrobial against Gram positive and negative bacteria, by slow release of oxygen radicals over a prolonged period of up to 72 h. It prevents and breaks down biofilm and may support healing by cellular signalling. Much clinical investigation remains to be delivered on RO therapy but there seem few disadvantages in its use and early clinical evaluations are extremely promising. SUMMARY: Managing complicated skin and soft tissue infections require more than just antibiotic treatment. Soft tissue infection healing is often compromised by underlying comorbidities and pathology and increasingly the presence of highly antimicrobial-resistant bacteria. This has been highlighted particularly in war and trauma soft tissue infection. The fundamentals of soft tissue infection repair require early surgical drainage and debridement, correction of compromised physiology and treatment of underlying conditions and appropriate antimicrobial treatment. RO therapy could be an important advance.

Update on the epidemiology of healthcare-acquired bacterial infections: focus on complicated skin and skin structure infections.

Healthcare-associated infections (HCAIs) are a threat to patient safety and cause substantial medical and economic burden in acute care and long-term care facilities. Risk factors for HCAIs include patient characteristics, the type of care and the setting. Local surveillance data and microbiological characterization are crucial tools for guiding antimicrobial treatment and informing efforts to reduce the incidence of HCAI. Skin and soft tissue infections, including superficial and deep incisional surgical site infections, are among the most frequent HCAIs. Other skin and soft tissue infections associated with healthcare settings include vascular access site infections, infected burns and traumas, and decubitus ulcer infections.

The clinical presentation, treatment and outcome of serologically confirmed paediatric Lyme disease in the Republic of Ireland over a 5-year period: a retrospective cohort study.

Lyme disease (LD) is the most common tick-borne illness in Europe. Population-based studies in European children are few. This study aimed to assess the incidence, clinical presentation, treatment and outcome of serologically confirmed paediatric LD in the Republic of Ireland over a 5-year period. A retrospective review of records from accredited laboratories performing Borrelia burgdorferi serological testing was undertaken. Proformas were distributed to clinicians of children and adolescents with positive Lyme serology. Data were requested regarding clinical presentation, treatment and outcome. Updated NICE guidelines were used to classify clinical cases. Serology testing for B. burgdorferi was performed on 2908 samples. Sixty-three (2.2%) children were two-tier positive, generating a crude annual incidence rate of 1.15/100,000. Proformas were returned for 55 (87%) and 47 met clinical and laboratory criteria for LD. Twenty-seven (57%) presented with non-focal symptoms (erythema migrans and/or influenza-like symptoms), and 20 (43%) with focal symptoms (cranial nerve involvement, 11; CNS involvement, 8; arthritis, 1). Median age at presentation was 8.2 (2.5-17.9) years. Seventeen (36%) acquired LD overseas. Twenty-five (83%) of the remaining 30 children acquired infection in the West/Northwest of Ireland. Full resolution of symptoms was reported in 97% of those with available data. Serologically confirmed LD in children is relatively rare in the Republic of Ireland. Ninety-eight percent of children tested were seronegative. Of the seropositive cases, 40% could have been diagnosed based on clinical findings alone. Neurological presentations (40%) were common. Full resolution of symptoms occurred in almost all (97%) where data were available.

Correction to: The early identification of disease progression in patients with suspected infection presenting to the emergency department: a multi-centre derivation and validation study.

In the publication of this article [1], there are two errors in contributing author affiliations. This has now been included in this correction article.

The early identification of disease progression in patients with suspected infection presenting to the emergency department: a multi-centre derivation and validation study.

BACKGROUND: There is a lack of validated tools to assess potential disease progression and hospitalisation decisions in patients presenting to the emergency department (ED) with a suspected infection. This study aimed to identify suitable blood biomarkers (MR-proADM, PCT, lactate and CRP) or clinical scores (SIRS, SOFA, qSOFA, NEWS and CRB-65) to fulfil this unmet clinical need. METHODS: An observational derivation patient cohort validated by an independent secondary analysis across nine EDs. Logistic and Cox regression, area under the receiver operating characteristic (AUROC) and Kaplan-Meier curves were used to assess performance. Disease progression was identified using a composite endpoint of 28-day mortality, ICU admission and hospitalisation > 10 days. RESULTS: One thousand one hundred seventy-five derivation and 896 validation patients were analysed with respective 28-day mortality rates of 7.1% and 5.0%, and hospitalisation rates of 77.9% and 76.2%. MR-proADM showed greatest accuracy in predicting 28-day mortality and hospitalisation requirement across both cohorts. Patient subgroups with high MR-proADM concentrations (≥ 1.54 nmol/L) and low biomarker (PCT < 0.25 ng/mL, lactate < 2.0 mmol/L or CRP < 67 mg/L) or clinical score (SOFA < 2 points, qSOFA < 2 points, NEWS < 4 points or CRB-65 < 2 points) values were characterised by a significantly longer length of hospitalisation (p < 0.001), rate of ICU admission (p < 0.001), elevated mortality risk (e.g. SOFA, qSOFA and NEWS HR [95%CI], 45.5 [10.0-207.6], 23.4 [11.1-49.3] and 32.6 [9.4-113.6], respectively) and a greater number of disease progression events (p < 0.001), compared to similar subgroups with low MR-proADM concentrations (< 1.54 nmol/L). Increased out-patient treatment across both cohorts could be facilitated using a derivation-derived MR-proADM cut-off of < 0.87 nmol/L (15.0% and 16.6%), with decreased readmission rates and no mortalities. CONCLUSIONS: In patients presenting to the ED with a suspected infection, the blood biomarker MR-proADM could most accurately identify the likelihood of further disease progression. Incorporation into an early sepsis management protocol may therefore aid rapid decision-making in order to either initiate, escalate or intensify early treatment strategies, or identify patients suitable for safe out-patient treatment.

A Phase 3, Randomized, Double-Blind, Multicenter Study to Evaluate the Safety and Efficacy of Intravenous Iclaprim Vs Vancomycin for the Treatment of Acute Bacterial Skin and Skin Structure Infections Suspected or Confirmed to be Due to Gram-Positive Pathogens: REVIVE-1.

Background: Our objective in this study was to demonstrate the safety and efficacy of iclaprim compared with vancomycin for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSIs). Methods: REVIVE-1 was a phase 3, 600-patient, double-blinded, randomized (1:1), active-controlled trial among patients with ABSSSI that compared the safety and efficacy of iclaprim 80 mg fixed dose with vancomycin 15 mg/kg, both administered intravenously every 12 hours for 5-14 days. The primary endpoint of this study was a ≥20% reduction in lesion size (early clinical response [ECR]) compared with baseline among patients randomized to iclaprim or vancomycin at the early time point (ETP), 48 to 72 hours after the start of administration of study drug in the intent-to-treat population. Results: ECR among patients who received iclaprim and vancomycin at the ETP was 80.9% (241 of 298) of patients receiving iclaprim compared with 81.0% (243 of 300) of those receiving vancomycin (treatment difference, -0.13%; 95% confidence interval, -6.42%-6.17%). Iclaprim was well tolerated in the study, with most adverse events categorized as mild. Conclusions: Iclaprim achieved noninferiority (10% margin) at ETP compared with vancomycin and was well tolerated in this phase 3 clinical trial for the treatment of ABSSSI. Based on these results, iclaprim appears to be an efficacious and safe treatment for ABSSSI suspected or confirmed to be due to gram-positive pathogens. Clinical Trials Registration: NCT02600611.

A Phase 3, Randomized, Double-Blind, Multicenter Study To Evaluate the Safety and Efficacy of Intravenous Iclaprim versus Vancomycin for Treatment of Acute Bacterial Skin and Skin Structure Infections Suspected or Confirmed To Be Due to Gram-Positive Pathogens (REVIVE-2 Study).

Iclaprim is a novel diaminopyrimidine antibiotic that may be an effective and safe treatment for serious skin infections. The safety and effectiveness of iclaprim were assessed in a global phase 3, double-blind, randomized, active-controlled trial. Six hundred thirteen adults with acute bacterial skin and skin structure infections (ABSSSIs) suspected or confirmed to be due to Gram-positive pathogens were randomized to iclaprim (80 mg) or vancomycin (15 mg/kg of body weight), both of which were administered intravenously every 12 h for 5 to 14 days. The primary endpoint was a ≥20% reduction in lesion size compared with that at the baseline at 48 to 72 h after the start of administration of study drug in the intent-to-treat population. Among patients randomized to iclaprim, 78.3% (231 of 295) met this primary endpoint, whereas 76.7% (234 of 305) of those receiving vancomycin met this primary endpoint (difference, 1.58%; 95% confidence interval, -5.10% to 8.26%). This met the prespecified 10% noninferiority margin. Iclaprim was well tolerated, with most adverse events being categorized as mild. In conclusion, iclaprim was noninferior to vancomycin in this phase 3 clinical trial for the treatment of acute bacterial skin and skin structure infections. On the basis of these results, iclaprim may be an efficacious and safe treatment for skin infections suspected or confirmed to be due to Gram-positive pathogens. (This trial has been registered at ClinicalTrials.gov under identifier NCT02607618.).

Lyme disease: diagnosis and management.

Lyme disease (borreliosis) is a tick-borne bacterial infection caused by the spirochaete Borrelia burgdoferi, transmitted by hard-backed Ixodes ticks. Actual numbers of cases are increasing and it appears that the distribution across the UK is widening; however, it occurs most frequently in area of woodland, with temperate climate. It typically presents in mid to late summer. Lyme disease is a multisystem disease. The nervous system is the second most commonly affected system after the skin. Other systemic manifestations, such as carditis, keratitis, uveitis and inflammatory arthritis, rarely occur in European Lyme disease. In 2018, the National Institute for Health and Care Excellence has updated its guidelines on the diagnosis and management of Lyme disease. Here, we highlight important aspects of this guidance and provide a more detailed review of the clinical spectrum of neuroborreliosis, illustrated by cases we have seen.

Reactive oxygen therapy: a novel therapy in soft tissue infection.

PURPOSE OF REVIEW: The global burden of disease in skin and soft tissue lesions is enormous. Many chronic, poorly healing lesions get treated with antibiotics despite the lack of evidence for long-term antibiotics. There is a global antibiotic resistance crisis driven largely by inappropriate use of large volumes of antibiotics. One solution is to reduce the selection pressure on bacteria by reducing the volume of antibiotic use in medicine, agriculture and the environment. There are few novel antimicrobials. One of the only novel agents to reach clinical use is one using reactive oxygen species (ROS), oxygen radicals, as an antimicrobial mechanism. RECENT FINDINGS: ROS can be delivered to the site of infection in various formats. ROS is highly antimicrobial against Gram-positive and negative bacteria, viruses and fungi. It also prevents and breaks down biofilm. These functions make ROS highly suitable for chronic inflammatory conditions, where antibiotics are frequently overused and relatively ineffective: chronic wounds, ulcers and burns; but also possibly mucosal infections in the respiratory and urinary tracts and in prosthetic device infection. ROS could also have an important role in infection prevention and antimicrobial stewardship. SUMMARY: Early clinical data support ROS treatment in skin and soft tissue lesions to reduce bacterial bioburden and biofilm in critical colonization and in preventing surgical site infection, although further trials of ROS in soft tissue infection would be helpful and research in ROS use at other clinical sites might support many novel clinical indications.

Reactive oxygen species (ROS) and wound healing: the functional role of ROS and emerging ROS-modulating technologies for augmentation of the healing process.

Reactive oxygen species (ROS) play a pivotal role in the orchestration of the normal wound-healing response. They act as secondary messengers to many immunocytes and non-lymphoid cells, which are involved in the repair process, and appear to be important in coordinating the recruitment of lymphoid cells to the wound site and effective tissue repair. ROS also possess the ability to regulate the formation of blood vessels (angiogenesis) at the wound site and the optimal perfusion of blood into the wound-healing area. ROS act in the host's defence through phagocytes that induce an ROS burst onto the pathogens present in wounds, leading to their destruction, and during this period, excess ROS leakage into the surrounding environment has further bacteriostatic effects. In light of these important roles of ROS in wound healing and the continued quest for therapeutic strategies to treat wounds in general and chronic wounds, such as diabetic foot ulcers, venous and arterial leg ulcers and pressure ulcers in particular, the manipulation of ROS represents a promising avenue for improving wound-healing responses when they are stalled. This article presents a review of the evidence supporting the critical role of ROS in wound healing and infection control at the wound site, and some of the new emerging concepts associated with ROS modulation and its potential in improving wound healing are discussed.

Antimicrobial stewardship in wound care: a Position Paper from the British Society for Antimicrobial Chemotherapy and European Wound Management Association.

BACKGROUND: With the growing global problem of antibiotic resistance it is crucial that clinicians use antibiotics wisely, which largely means following the principles of antimicrobial stewardship (AMS). Treatment of various types of wounds is one of the more common reasons for prescribing antibiotics. OBJECTIVES: This guidance document is aimed at providing clinicians an understanding of: the basic principles of why AMS is important in caring for patients with infected wounds; who should be involved in AMS; and how to conduct AMS for patients with infected wounds. METHODS: We assembled a group of experts in infectious diseases/clinical microbiology (from the British Society for Antimicrobial Chemotherapy) and wound management (from the European Wound Management Association) who, after thoroughly reviewing the available literature and holding teleconferences, jointly produced this guidance document. RESULTS: All open wounds will be colonized with bacteria, but antibiotic therapy is only required for those that are clinically infected. Therapy is usually empirical to start, but definitive therapy should be based on results of appropriately collected specimens for culture. When prescribed, it should be as narrowly focused, and administered for the shortest duration, as possible. AMS teams should be interdisciplinary, especially including specialists in infection and pharmacy, with input from administrative personnel, the treating clinicians and their patients. CONCLUSIONS: Available evidence is limited, but suggests that applying principles of AMS to the care of patients with wounds should help to reduce the unnecessary use of systemic or topical antibiotic therapy and ensure the safest and most clinically effective therapy for infected wounds.

A Phase III, randomized, controlled, non-inferiority trial of ceftaroline fosamil 600 mg every 8 h versus vancomycin plus aztreonam in patients with complicated skin and soft tissue infection with systemic inflammatory response or underlying comorbidities.

OBJECTIVES: Increasing the ceftaroline fosamil dose beyond 600 mg every 12 h may provide additional benefit for patients with complicated skin and soft tissue infections (cSSTIs) with severe inflammation and/or reduced pathogen susceptibility. A Phase III multicentre, randomized trial evaluated the safety and efficacy of ceftaroline fosamil 600 mg every 8 h in this setting. METHODS: Adult patients with cSSTI and systemic inflammation or comorbidities were randomized 2:1 to intravenous ceftaroline fosamil (600 mg every 8 h) or vancomycin (15 mg/kg every 12 h) plus aztreonam (1 g every 8 h) for 5-14 days. Clinical cure was assessed at the test of cure (TOC) visit (8-15 days after the final dose) in the modified ITT (MITT) and clinically evaluable (CE) populations. Non-inferiority was defined as a lower limit of the 95% CI around the treatment difference greater than -10%. An MRSA-focused expansion period was initiated after completion of the main study. Clinicaltrials.gov registration numbers NCT01499277 and NCT02202135. RESULTS: Clinical cure rates at TOC demonstrated non-inferiority of ceftaroline fosamil 600 mg every 8 h versus vancomycin plus aztreonam in the MITT and CE populations: 396/506 (78.3%) versus 202/255 (79.2%) patients (difference -1.0%, 95% CI -6.9, 5.4) and 342/395 (86.6%) versus 180/211 (85.3%) patients (difference 1.3%, 95% CI -4.3, 7.5), respectively. In the expansion period, 3/4 (75%) patients treated with ceftaroline fosamil were cured at TOC. The frequency of adverse events was similar between groups. CONCLUSIONS: Ceftaroline fosamil 600 mg every 8 h was effective for cSSTI patients with evidence of systemic inflammation and/or comorbidities. No new safety signals were identified.

Alternative clinical indications for novel antibiotics licensed for skin and soft tissue infection?

PURPOSE OF REVIEW: A number of novel antibiotics in different classes have been registered and licensed in recent years for complicated skin and soft tissue infections or acute bacterial skin and skin structure infections. Many of these have activity against resistant gram-positive bacteria (linezolid, daptomycin, oritavancin, dalbavancin and tedizolid). In addition, two have gram-negative activity (ceftaroline and tigecycline). The licence for the clinical use of these agents is very narrow, but the clinical need is much broader. This is a personal opinion of the prospective clinical roles for these novel antibiotics. RECENT FINDINGS: All were found to be noninferior to standard comparators in registration trials. There are few data on their use in other clinical conditions outside the narrow confines of the registration trials. 'Off-label' use is likely to be more common than the licensed use, and data need to be collected on clinical and microbiological efficacy and adverse effects in real life. SUMMARY: There is now a wide range of antibiotics for treating complicated skin and soft tissue infections or acute bacterial skin and skin structure infections, and they all have a role in different clinical scenarios. Use in nonlicensed situations needs to be assessed.

Novel antibiotic treatment for skin and soft tissue infection.

PURPOSE OF REVIEW: Acute bacterial skin and skin structure infection (ABSSSI) is a common and significant indication for antibiotic treatment. The microbial aetiology is becoming more resistant to available antibiotics and the treatment of patients is additionally challenged by extremes of age, obesity, diabetes and other co-morbidities. This review examines recent antimicrobial developments. RECENT FINDINGS: In many parts of the world, multidrug-resistant (MDR) staphylococci are the predominant cause of ABSSSI in both the community and in hospital. Increasing resistance in Gram-negative organisms presents problems in the management of surgical-site infections. Most new antibiotics have been developed to treat MDR Gram-positive bacteria and there are few agents to treat infections caused by MDR Gram-negative pathogens. SUMMARY: A number of novel agents are available clinically, with other agents of related chemical structure under development. There are no entirely new classes of antibiotics. Maintaining the efficacy of antimicrobial treatment require effective antibiotic stewardship, good infection prevention and the development of further new antibiotics.

Prosthetic joint infection: managing infection in a bionic era.

There is increasing demand for prosthetic joint surgery and patients are becoming more challenging due to an ageing population often with comorbidities and immunosuppression. While prosthetic joint infection (PJI) rates are generally low, infection can be catastrophic for the patient and hence prevention of infection is critical. Infection, when it does occur, is further complicated by the global rise in antimicrobial resistance. This article introduces a series of papers on the epidemiology of PJI, its diagnosis, use of novel inflammatory markers and molecular techniques, clinical presentation, importance of biofilms, treatment guidelines and, finally, various strategies and novel antibiotic treatment regimens.

Branching ratios in reactions of OH radicals with methylamine, dimethylamine, and ethylamine.

The branching ratios for the reaction of the OH radical with the primary and secondary alkylamines: methylamine (MA), dimethylamine (DMA), and ethylamine (EA), have been determined using the technique of pulsed laser photolysis-laser-induced fluorescence. Titration of the carbon-centered radical, formed following the initial OH abstraction, with oxygen to give HO2 and an imine, followed by conversion of HO2 to OH by reaction with NO, resulted in biexponential OH decay traces on a millisecond time scale. Analysis of the biexponential curves gave the HO2 yield, which equaled the branching ratio for abstraction at αC-H position, r(αC-H). The technique was validated by reproducing known branching ratios for OH abstraction for methanol and ethanol. For the amines studied in this work (all at 298 K): r(αC-H,MA) = 0.76 ± 0.08, r(αC-H,DMA) = 0.59 ± 0.07, and r(αC-H,EA) = 0.49 ± 0.06 where the errors are a combination in quadrature of statistical errors at the 2σ level and an estimated 10% systematic error. The branching ratios r(αC-H) for OH reacting with (CH3)2NH and CH3CH2NH2 are in agreement with those obtained for the OD reaction with (CH3)2ND (d-DMA) and CH3CH2ND2 (d-EA): r(αC-H,d-DMA) = 0.71 ± 0.12 and r(αC-H,d-EA) = 0.54 ± 0.07. A master equation analysis (using the MESMER package) based on potential energy surfaces from G4 theory was used to demonstrate that the experimental determinations are unaffected by formation of stabilized peroxy radicals and to estimate atmospheric pressure yields. The branching ratio for imine formation through the reaction of O2 with α carbon-centered radicals at 1 atm of N2 are estimated as r(CH2NH2) = 0.79 ± 0.15, r(CH2NHCH3) = 0.72 ± 0.19, and r(CH3CHNH2) = 0.50 ± 0.18. The implications of this work on the potential formation of nitrosamines and nitramines are briefly discussed.

Molecular analysis of an outbreak of lethal postpartum sepsis caused by Streptococcus pyogenes.

Sepsis is now the leading direct cause of maternal death in the United Kingdom, and Streptococcus pyogenes is the leading pathogen. We combined conventional and genomic analyses to define the duration and scale of a lethal outbreak. Two postpartum deaths caused by S. pyogenes occurred within 24 h; one was characterized by bacteremia and shock and the other by hemorrhagic pneumonia. The women gave birth within minutes of each other in the same maternity unit 2 days earlier. Seven additional infections in health care and household contacts were subsequently detected and treated. All cluster-associated S. pyogenes isolates were genotype emm1 and were initially indistinguishable from other United Kingdom emm1 isolates. Sequencing of the virulence gene sic revealed that all outbreak isolates had the same unique sic type. Genome sequencing confirmed that the cluster was caused by a unique S. pyogenes clone. Transmission between patients occurred on a single day and was associated with casual contact only. A single isolate from one patient demonstrated a sequence change in sic consistent with longer infection duration. Transmission to health care workers was traced to single clinical contacts with index cases. The last case was detected 18 days after the first case. Following enhanced surveillance, the outbreak isolate was not detected again. Mutations in bacterial regulatory genes played no detectable role in this outbreak, illustrating the intrinsic ability of emm1 S. pyogenes to spread while retaining virulence. This fast-moving outbreak highlights the potential of S. pyogenes to cause a range of diseases in the puerperium with rapid transmission, underlining the importance of immediate recognition and response by clinical infection and occupational health teams.

Tigecycline: an antibiotic for the twenty-first century.

This Supplement in the Journal of Antimicrobial Chemotherapy comprises a series of papers reporting on 'real-life' clinical experience with tigecycline. The data reported are derived from five European observational studies on the use of tigecycline, either as monotherapy or in combination with other antibiotics, for the treatment of complicated skin and soft-tissue infections or complicated intra-abdominal infections. Taken together, this collection of articles gives clinical insight into the use of tigecycline for the treatment of complicated infections.

Antibiotic management and early discharge from hospital: an economic analysis.

OBJECTIVES: To evaluate potential costs and savings from implementing an evaluation tool that uses bedside review of antibiotic use and infection management to assess whether patients with infections in acute medical and surgical wards could have their antibiotic regimen changed and be safely managed out of hospital. METHODS: The tool was implemented in 30 acute wards in five UK hospital trusts. Data were collected on demographic variables, diagnosis, social situation, hospital stay and all current antibiotic prescribing for 291 patients. A physician and pharmacist assessed antibiotic therapy and feasibility of discharge. Resource use was measured for each patient, unit costs attached, and mean and total costs of implementing recommendations were calculated. RESULTS: Implementation of these recommendations could reduce total inpatient days by 494 at a saving of £186 731, and save £20 215 from adjustment of antibiotic therapy. Additional costs were associated with implementation of the assessment (£2468), community support (£6227) and outpatient parenteral antimicrobial therapy (£5616). As a result, the net potential savings would be £192 635 in total or £662 (95% CI: £393, £930) for every patient assessed. Excluding eight patients with the highest potentially avoidable inpatient stays (>15 days), mean savings would fall to £363 per patient assessed but remain highly significant (95% CI: £261, £465). CONCLUSIONS: Careful assessment of antibiotic use in acute wards has the potential to reduce the use and cost of antibiotics, and length of stay. Added costs of assessment and out-of-hospital support services would offset a small proportion of these potential savings. Randomized studies are now needed to test these results.

Autochthonous tick-borne encephalitis in the United Kingdom: A second probable human case and local eco-epidemiological findings.

Tick-borne encephalitis (TBE) is a neurotropic flaviviral disease. TBE was previously thought to be absent from the United Kingdom. We report the second probable case of United Kingdom-acquired TBE and demonstrate deer TBE-serocomplex seropositivity in the surrounding area, providing further evidence of the presence of TBE in England.