HIV and Pneumocystis Jiroveci Pneumonia (PJP) Managed With Extracorporeal Membrane Oxygenation (ECMO).

Presentation A 40-year-old Irish female presented with a new diagnosis of HIV, advanced immunosuppression and severe respiratory failure. Diagnosis Patient was subsequently diagnosed with Pneumocystis jiroveci Pneumonia (PJP). Treatment The patient was treated for HIV and PJP and required mechanical ventilation. She continued to deteriorate and veno-venous Extracorporeal Membrane Oxygenation (V-V ECMO) was deployed in her management after 18 days of mechanical ventilation. Conclusion HIV presenting with extensive pneumonia secondary to PJP and advanced immunosuppression is still a treatable condition. All available respiratory support including ECMO should be considered for patients even if they have been on mechanical ventilation for more than 7 days.

National Guidelines on the Provision of Outpatient Parenteral Antimicrobial Therapy (OPAT).

Aim Outpatient parenteral antimicrobial therapy (OPAT) is an option in patients who require parenteral antimicrobial administration and are clinically well enough for hospital discharge. This is an update of the Irish National OPAT guidelines which were last reviewed in 2011. Methods The guideline was devised through a collaborative process with the national OPAT Working Group and a review of the literature. It is intended for clinicians who prescribe any intravenous (IV) antimicrobials outside of the inpatient setting in the Republic of Ireland. Results Patient care while on OPAT should be provided by a designated OPAT service, with clear managerial and clinical governance lines of responsibility. It should be conducted using a team approach with a clinical lead on each site either as an infection specialist, or a general medical physician with infection specialist input and an OPAT nurse. An antimicrobial pharmacist is also desirable. Several factors must be considered when assessing patient's suitability for OPAT including exclusion criteria, infection-specific factors, and patient specific factors such as physical, social and logistic criteria. Conclusion This updated guideline advocates a more individualised OPAT approach, with the recognition that specific antimicrobials and/or specific delivery models may be more appropriate for certain patient groups. Full guidelines are available through www.opat.ie.

Antifungal stewardship in critical care: Implementing a diagnostics-driven care pathway in the management of invasive candidiasis.

BACKGROUND: Invasive candidiasis (IC) is the most common invasive fungal disease in patients admitted to critical care and is associated with high mortality rates. Diagnosis can be delayed by the poor sensitivity of culture-based methods, leading to unnecessary use of empirical antifungal therapy (EAFT). The fungal biomarker (1-3)-ß-d-glucan (BDG) has been shown to aid in the diagnosis of IC in critical care and has been incorporated into antifungal stewardship (AFS) programmes. AIM: To describe our experience using a diagnostics-driven AFS programme incorporating the fungal biomarker BDG, analyse its impact on antifungal therapy (AFT), and gain an improved understanding of the epidemiology of IC in our critical care unit (CrCU). METHODS: An AFS care pathway incorporating BDG was introduced in the CrCU in St James's Hospital, Dublin. Following an educational programme, compliance with the pathway was prospectively audited between December 1st, 2017 and July 31st, 2018. RESULTS AND CONCLUSION: One hundred and nine AFT episodes were included, of which 95 (87%) had a BDG sent. Of those with BDG results available at the time of decision-making, 38 (63%) were managed in accordance with the care pathway. In compliant episodes without IC, median EAFT duration was 5.5 days [IQR 4-7] and no increase in mortality or subsequent IC was observed. Although adopting a diagnostics-driven approach was found to be useful in the cohort of patients with BDG results available, the use of once-weekly BDG testing did not result in an observed reduction in the consumption of anidulafungin, highlighting an important limitation of this approach.

Impact of a diagnostics-driven antifungal stewardship programme in a UK tertiary referral teaching hospital.

Objectives: A concise invasive candidosis guideline (based on the ESCMID candidaemia guideline) utilizing an informative biomarker [serum ß-1-3-d-glucan (BDG)] was developed in 2013 by an antifungal stewardship (AFS) team and implemented with the help of an AFS champion in 2014. The main aims of the AFS programme were to reduce inappropriate use of antifungals and improve patient outcomes. The aim of this project was to evaluate the compliance of the ICU teams with the invasive candidosis guideline and the impact of the AFS programme on mortality and antifungal consumption on the ICUs (total of 71 beds). Methods: All patients who were prescribed micafungin for suspected or proven invasive candidosis during 4 month audit periods in 2014 and 2016 were included. Prescriptions and patient records were reviewed against the guideline. Antifungal consumption and mortality data were analysed. Results: The number of patients treated for invasive candidosis decreased from 39 in 2014 to 29 in 2016. This was mainly due to the reduction in patients initiated on antifungal therapy inappropriately: 18 in 2014 and 2 in 2016. Antifungal therapy was stopped following negative biomarker results in 12 patients in 2014 and 10 patients in 2016. Crude mortality due to proven or probable invasive candidosis decreased to 19% from 45% over the period 2003-07. Antifungal consumption reduced by 49% from 2014 to 2016. Conclusions: The AFS programme was successful in reducing the number of inappropriate initiations of antifungals by 90%. Concurrently, mortality due to invasive candidosis was reduced by 58%. BDG testing can guide safe cessation of antifungals in ICU patients at risk of invasive candidosis.

Invasive pulmonary aspergillosis is associated with adverse clinical outcomes in critically ill patients receiving veno-venous extracorporeal membrane oxygenation.

To identify the incidence, risk factors and impact on long-term survival of invasive pulmonary aspergillosis (IPA) and Aspergillus colonisation in patients receiving vv-extracorporeal membrane oxygenation (ECMO). A retrospective evaluation was performed of patients receiving vv-ECMO at a tertiary hospital in Manchester (UK) between January 2012 and December 2016. Data collected included epidemiological data, microbiological cultures, radiographic findings and outcomes. Cases were classified as proven IPA, putative IPA or Aspergillus colonisation according to a validated clinical algorithm. One hundred thirty-four patients were supported with vv-ECMO, median age of 45.5 years (range 16.4-73.4). Ten (7%) patients had putative IPA and nine (7%) had Aspergillus colonisation. Half of the patients with putative IPA lacked classical host risk factors for IPA. The median number of days on ECMO prior to Aspergillus isolation was 5 days. Immunosuppression and influenza A infection were significantly associated with developing IPA in a logistic regression model. Cox regression model demonstrates a three times greater hazard of death associated with IPA. Overall 6-month mortality rate was 38%. Patients with putative IPA and colonised patients had a 6-month mortality rate of 80 and 11%, respectively. Immunosuppression and influenza A infection are independent risk factors for IPA. IPA, but not Aspergillus colonisation, is associated with high long-term mortality in patients supported with vv-ECMO.

Outpatient parenteral antimicrobial therapy (OPAT) in the Republic of Ireland: results of a national survey.

Outpatient parenteral antimicrobial therapy (OPAT) services are not well developed in the Republic of Ireland. A national programme is being instituted to standardise care. This survey aims to assess the current use of outpatient intravenous antibiotics and to quantify the needs that physicians identify in the development of a national programme. General medical consultant physicians and clinical microbiology consultants were contacted through the Royal College of Physicians of Ireland (RCPI) from April to June 2012. Data were analysed using SPSS version 20. A total of 512 physicians were contacted, of which 55 (10.7 %) responded. The majority, 38/55 (69 %), practice general internal medicine in combination with a medical specialty, 2 (4 %) general internal medicine alone, 8 (15 %) clinical microbiology and 7 (13 %) a medical specialty alone. Of those practising a medical specialty, 12 (27 %) practice infectious diseases. Seventy-four percent reported having discharged patients with intravenous antibiotics; however, 47 % did not have a designated service available. Of those with no service, 100 % identified a need for these resources. Of those responsible for an OPAT service, 56 % had not audited their service. The most common indications were skin and soft tissue infections, osteomyelitis and respiratory tract infection. Flucloxacillin was the most commonly reported antibiotic. Eleven percent responded that they never monitor laboratory studies for patients discharged with intravenous antibiotics. While OPAT services in Ireland are not well developed, patients are being discharged with intravenous antibiotics. This survey underscores the need to develop the national programme to standardise care and ensure patients receive safe and efficient therapy.

Dilemmas in the management of syphilis.

A recent U.S. survey demonstrated wide variation in the management of syphilis. 25/31 (73.5%) Consultants and Specialist Registrars in Infectious Diseases and Genitourinary Medicine, in Ireland were surveyed. 23 (92%) treat more than 50 HIV patients a year, 18 (72%) had been consulted on a patient with syphilis in the last year. With secondary syphilis, 13 (52%) give 3 doses of benzathine penicillin, while 10 (40%) give one, no statistical difference between consultants and SpRs (p = 0.9). Significant variation in the investigation and management of syphilis in Ireland was identified. There is a need for the development of Irish national guidelines on the management of syphilis.

Long-term neurological follow-up of HIV-positive patients diagnosed with syphilis.

No cerebrospinal fluid (CSF) abnormalities are found in HIV-positive patients in long-term follow-up after standard syphilis treatment. Syphilis has been reported to have immunological effects on HIV infection and HIV is known to modulate both the manifestations of syphilis and the serological response to therapy. HIV-positive patients who had been diagnosed with and treated for syphilis prior to 2007 were identified. Patients were consented for lumbar puncture. Serum HIV viral load, CD4 count and CSF were recorded. Thirty-five patients with previously diagnosed and treated syphilis underwent lumbar puncture. Thirty-four patients had a normal neurological exam. Only one patient had an abnormal mean white cell count (10.7 cells per high-power field). The finding that those with previously diagnosed syphilis had normal CSF and clinical findings is reassuring and supports the practice of using standard syphilis therapy in HIV-positive patients.

Syphilis resurgence in Dublin, Ireland.

A large outbreak of syphilis was reported in Dublin, Ireland, in 2001. The mean age of patients in 2001 was 35 years and 22.5% of patients were HIV-positive. The number of new cases decreased from 2003 on, however, new diagnoses have again increased. All positive syphilis serology results from 2007-09 were identified. Patients were included if they had a newly positive syphilis serology or, in the case of patients with previously treated syphilis, had a four-fold rise in rapid plasma reagin titre. Four hundred and thirty-nine new diagnoses of syphilis were made. The mean age of patients at diagnosis was 35.7 years (range 17-73 years). Four hundred and twelve (93.8%) cases occurred in men. Three hundred and eighty-one (86.8%) cases occurred in men who have sex with men (MSM). The estimated crude incidence rate among MSM is 378.16 per 100,000 population. Where known, 126/421 (28.7%) occurred in HIV-positive patients. Sixty-eight (15.5%) episodes of syphilis infection were diagnosed in patients who had had previously been diagnosed and treated for syphilis; 43/68 (63.2%) cases of re-infection occurred in HIV-positive patients. The rising number of syphilis diagnoses and high associated HIV co-infection rate is concerning and prevention efforts must continue to decrease the number of new syphilis cases.

Room for improvement--syphilis; knowledge and delayed diagnosis among sexual health clinic attendees.

Cases of early infectious syphilis are increasing in Ireland. A questionnaire distributed to sexual health clinic attendees assessed syphilis knowledge. A telephone survey in patients with secondary syphilis explored potential delays in diagnosis. 272 questionnaires were completed. 54% of respondents were male, 222 (81.6%) were Irish.31/268 (12%) who stated their sexual orientation were men who have sex with men (MSM). 226 (83%) had heard of syphilis. MSM had better knowledge compared to heterosexual males (p<0.05). Contact details were available for 60 patients with secondary syphilis. 37 patients were surveyed. 31/37 (84%) recalled symptoms prior to diagnosis, mean duration of symptoms 53 days (range 7-168). 23/37 (62%) reported consulting at least one physician before attending sexual health services. 12/23 (52%) were given an alternate or no diagnosis. Greater awareness of syphilis signs and symptoms is needed amongst patients and healthcare providers to prevent delayed diagnosis leading to ongoing transmission.

Zoonotic transmission of Streptococcus equi subsp. zooepidemicus from a dog to a handler.

This is, to the best of our knowledge, the first case report to describe the apparent transmission of Streptococcus equi subsp. zooepidemicus from an infected dog to a handler who subsequently developed severe systemic infection. Characterization of the haemolytic streptococci isolated from both the patient and the dog, by phenotypic and molecular analysis, confirmed the canine and human isolates were identical.

Generalised tetanus in an unvaccinated adult.

A 76-year-old previously well farmer presented having caught his left index finger in a gate. He gave no history of prior tetanus vaccination. The patient was treated in the emergency department; the wound cleaned, sutured and he was given tetanus toxoid prior to discharge. Eleven days later he represented unable to open his mouth. On examination he was noted to have trismus, generalised muscle spasms, diaphoresis and emotional lability and he was diagnosed with generalised tetanus.

Enzymic cross-linkage of monomeric extensin precursors in vitro.

Rapidly growing tomato (Lycopersicon esculentum) cell suspension cultures contain transiently high levels of cell surface, salt-elutable, monomeric precursors to the covalently cross-linked extensin network of the primary cell wall. Thus, we purified a highly soluble monomeric extensin substrate from rapidly growing cells, and devised a soluble in vitro cross-linking assay based on Superose-6 fast protein liquid chromatography separation, which resolved extensin monomers from the newly formed oligomers within 25 minutes. Salt elution of slowly growing (early stationary phase) cells yielded little or no extensin monomers but did give a highly active enzymic preparation that specifically cross-linked extensin monomers in the presence of hydrogen peroxide, judging from: (a) a decrease in the extensin monomer peak on fast protein liquid chromatography gel filtration, (b) appearance of oligomeric peaks, and (c) direct electron microscopical observation of the cross-linked oligomers. The cross-linking reaction had a broad pH optimum between 5.5 and 6.5. An approach to substrate saturation of the enzyme required extensin monomer concentrations of 20 to 40 milligrams per milliliter. Preincubation with catalase completely inhibited the cross-linking reaction, which was highly dependent on hydrogen peroxide and optimal at 15 to 50 micromolar. We therefore identified the cross-linking activity as extensin peroxidase.

High molecular weight proteoglycans biosynthesized in culture by pigeon aortas.

The properties of aortic proteoglycans synthesized in vitro were examined to demonstrate synthesis of intact proteoglycans by aortic tissue in culture and to compare labeling and synthetic rates of two different populations of proteoglycan. Following 3, 6, or 9 h of incubation in medium containing [35S]sodium sulfate and [3H]serine, the tissue was extracted with 4.0 M guanidine hydrochloride containing protease inhibitors. Extracts were chromatographed on Sepharose CL-4B and subjected to buoyant density centrifugation under dissociative conditions. Radioactive precursors were incorporated into two major populations of aortic proteoglycan, one of high molecular weight eluting near the void volume of Sepharose CL-4B (Proteoglycan I) and one of lower molecular weight (Proteoglycan II) having a Kav of 0.40-0.44. The radioactively labeled proteoglycans were localized at densities 1.50-1.56 g/ml (Preparation 1) and 1.43-1.49 g/ml (Preparation 2) following CsCl buoyant density centrifugation. Both proteoglycan populations had increased incorporation of 35S and 3H over time. At all times the lower molecular weight proteoglycan had a higher specific activity (dpm 35S and 3H/micrograms hexuronic acid). At 3, 6, and 9 h, the specific activity of Proteoglycan II was 8.2-, 6.7- and 3.0-fold higher than Proteoglycan I using 35S and 13.0-, 8.1- and 2.7-fold higher using 3H, suggesting different synthetic rates for the two proteoglycans. The results illustrate synthesis of intact proteoglycans during short-term artery culture. The proteoglycan types have size and buoyant density characteristics as described for artery, but based upon changes in specific activity ratios, the two proteoglycan populations differ in rates of synthesis.

Comparative metabolism of aspartame in experimental animals and humans.

Aspartame [SC-18862; 3-amino-N-(alpha-carboxyphenethyl) succinamic acid, methyl ester, the methyl ester of aspartylphenylalanine] is a sweetening agent that organoleptically has about 180 times the sweetness of sugar. The metabolism of aspartame has been studied in mice, rats, rabbits, dogs, monkeys, and humans. The compound was digested in all species in the same way as are natural constituents of the diet. Hydrolysis of the methyl group by intestinal esterases yielded methanol, which was oxidized in the one-carbon metabolic pool to CO2. The resultant dipeptide was split at the mucosal surface by dipeptidases and the free amino acids were absorbed. The aspartic acid moiety was transformed in large part to CO2 through its entry into the tricarboxylic acid cycle. Phenylalanine was primarily incorporated into body protein either unchanged or as its major metabolite, tyrosine.