Ymkje Stienstra

Effect of Azithromycin Maintenance Treatment on Infectious Exacerbations Among Patients With Non-Cystic Fibrosis Bronchiectasis The BAT Randomized Controlled Trial

IMPORTANCE Macrolide antibiotics have been shown beneficial in cystic fibrosis (CF) and diffuse panbronchiolitis, and earlier findings also suggest a benefit in non-CF bronchiectasis. OBJECTIVE To determine the efficacy of macrolide maintenance treatment for adults with non-CF bronchiectasis. DESIGN, SETTING, AND PARTICIPANTS The BAT (Bronchiectasis and Long-term Azithromycin Treatment) study, a randomized, double-blind, placebo-controlled trial conducted between April 2008 and September 2010 in 14 hospitals in The Netherlands among 83 outpatients with non-CF bronchiectasis and 3 or more lower respiratory tract infections in the preceding year. INTERVENTIONS Azithromycin (250 mg daily) or placebo for 12 months. MAIN OUTCOME MEASURES Number of infectious exacerbations during 12 months of treatment. Secondary end points included lung function, sputum bacteriology, inflammatory markers, adverse effects, symptom scores, and quality of life. RESULTS Forty-three participants (52%) received azithromycin and 40 (48%) received placebo and were included in the modified intention-to-treat analysis. At end of study, the median number of exacerbations in the azithromycin group was 0 (interquartile range [IQR], 0-1), compared with 2 (IQR, 1-3) in the placebo group (P < .001). Thirty-two (80%) placebo-treated vs 20 (46%) azithromycin-treated individuals had at least 1 exacerbation (hazard ratio, 0.29 [95% CI, 0.16-0.51]). In a mixed-model analysis, change in forced expiratory volume in the first second of expiration (percent of predicted) over time differed between groups (F1,78.8 = 4.085, P = .047), with an increase of 1.03% per 3 months in the azithromycin group and a decrease of 0.10% per 3 months in the placebo group. Gastrointestinal adverse effects occurred in 40% of patients in the azithromycin group and in 5% in the placebo group (relative risk, 7.44 [95% CI, 0.97-56.88] for abdominal pain and 8.36 [95% CI, 1.10-63.15] for diarrhea) but without need for discontinuation of study treatment. A macrolide resistance rate of 88% was noted in azithromycin-treated individuals, compared with 26% in the placebo group. CONCLUSIONS AND RELEVANCE Among adults with non-CF bronchiectasis, the daily use of azithromycin for 12 months compared with placebo resulted in a lower rate of infectious exacerbations. This could result in better quality of life and might influence survival, although effects on antibiotic resistance need to be considered. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00415350.

Antimicrobial treatment for early, limited Mycobacterium ulcerans infection: a randomised controlled trial

BACKGROUND Surgical debridement was the standard treatment for Mycobacterium ulcerans infection (Buruli ulcer disease) until WHO issued provisional guidelines in 2004 recommending treatment with antimicrobial drugs (streptomycin and rifampicin) in addition to surgery. These recommendations were based on observational studies and a small pilot study with microbiological endpoints. We investigated the efficacy of two regimens of antimicrobial treatment in early-stage M ulcerans infection. METHODS In this parallel, open-label, randomised trial undertaken in two sites in Ghana, patients were eligible for enrolment if they were aged 5 years or older and had early (duration <6 months), limited (cross-sectional diameter <10 cm), M ulcerans infection confirmed by dry-reagent-based PCR. Eligible patients were randomly assigned to receive intramuscular streptomycin (15 mg/kg once daily) and oral rifampicin (10 mg/kg once daily) for 8 weeks (8-week streptomycin group; n=76) or streptomycin and rifampicin for 4 weeks followed by rifampicin and clarithromycin (7.5 mg/kg once daily), both orally, for 4 weeks (4-week streptomycin plus 4-week clarithromycin group; n=75). Randomisation was done by computer-generated minimisation for study site and type of lesion (ulceration or no ulceration). The randomly assigned allocation was sent from a central site by cell-phone text message to the study coordinator. The primary endpoint was lesion healing at 1 year after the start of treatment without lesion recurrence or extensive surgical debridement. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00321178. FINDINGS Four patients were lost to follow-up (8-week streptomycin, one; 4-week streptomycin plus 4-week clarithromycin, three). Since these four participants had healed lesions at their last assessment, they were included in the analysis for the primary endpoint. 73 (96%) participants in the 8-week streptomycin group and 68 (91%) in the 4-week streptomycin plus 4-week clarithromycin group had healed lesions at 1 year (odds ratio 2.49, 95% CI 0.66 to infinity; p=0.16, one-sided Fishers exact test). No participants had lesion recurrence at 1 year. Three participants had vestibulotoxic events (8-week streptomycin, one; 4-week streptomycin plus 4-week clarithromycin, two). One participant developed an injection abscess and two participants developed an abscess close to the initial lesion, which was incised and drained (all three participants were in the 4-week streptomycin plus 4-week clarithromycin group). INTERPRETATION Antimycobacterial treatment for M ulcerans infection is effective in early, limited disease. 4 weeks of streptomycin and rifampicin followed by 4 weeks of rifampicin and clarithromycin has similar efficacy to 8 weeks of streptomycin and rifampicin; however, the number of injections of streptomycin can be reduced by switching to oral clarithromycin after 4 weeks. FUNDING European Union (EU FP6 2003-INCO-Dev2-015476) and Buruli Ulcer Groningen Foundation.

Mycobacterium ulcerans disease

Mycobacterium ulcerans disease (Buruli ulcer) is an important health problem in several west African countries. It is prevalent in scattered foci around the world, predominantly in riverine areas with a humid, hot climate. We review the epidemiology, bacteriology, transmission, immunology, pathology, diagnosis and treatment of infections. M. ulcerans is an ubiquitous micro-organism and is harboured by fish, snails, and water insects. The mode of transmission is unknown. Lesions are most common on exposed parts of the body, particularly on the limbs. Spontaneous healing may occur. Many patients in endemic areas present late with advanced, severe lesions. BCG vaccination yields a limited, relatively short-lived, immune protection. Recommended treatment consists of surgical debridement, followed by skin grafting if necessary. Many patients have functional limitations after healing. Better understanding of disease transmission and pathogenesis is needed for improved control and prevention of Buruli ulcer.

Histopathologic features of Mycobacterium ulcerans infection.

Because of the emergence of Buruli ulcer disease, the World Health Organization launched a Global Buruli Ulcer Initiative in 1998. This indolent skin infection is caused by Mycobacterium ulcerans. During a study of risk factors for the disease in Ghana, adequate excisional skin-biopsy specimens were obtained from 124 clinically suspicious lesions. Buruli ulcer disease was diagnosed in 78 lesions since acid-fast bacilli (AFB) were found by histopathologic examination. Lesions with other diagnoses included filariasis (3 cases), zygomycosis (2 cases), ulcerative squamous cell carcinomas (2 cases), keratin cyst (1 case), and lymph node (1 case). Thirty-seven specimens that did not show AFB were considered suspected Buruli ulcer disease cases. Necrosis of subcutaneous tissues and dermal collagen were found more frequently in AFB-positive specimens compared with specimens from suspected case-patients (p<0.001). Defining histologic criteria for a diagnosis of Buruli ulcer disease is of clinical and public health importance since it would allow earlier treatment, leading to less deforming sequelae.

Risk factors for Buruli ulcer disease (Mycobacterium ulcerans infection) : Results from a case-control study in Ghana

BACKGROUND Morbidity due to Buruli ulcer disease (BUD), a cutaneous infection caused by Mycobacterium ulcerans, has been increasingly recognized in rural West Africa. The source and mode of transmission remain unknown. METHODS To identify BUD risk factors, we conducted a case-control study in 3 BUD-endemic districts in Ghana. We enrolled case patients with clinically diagnosed BUD and obtained skin biopsy specimens. M. ulcerans infection was confirmed by at least 1 of the following diagnostic methods: histopathologic analysis, culture, polymerase chain reaction, and Ziehl-Neelsen staining of a lesion smear. We compared characteristics of case patients with confirmed BUD with those of age- and community-matched control subjects using conditional logistic regression analysis. RESULTS Among 121 case patients with confirmed BUD, leg lesions (49%) or arm lesions (36%) were common. Male case patients were significantly more likely than female case patients to have lesions on the trunk (25% vs. 6%; P = .009). Multivariable modeling among 116 matched case-control pairs identified wading in a river as a risk factor for BUD (odds ratio [OR], 2.69; 95% confidence interval [CI], 1.27-5.68; P = .0096). Wearing a shirt while farming (OR, 0.27; 95% CI, 0.11-0.70; P = .0071), sharing indoor living space with livestock (OR, 0.36; 95% CI, 0.15-0.86; P = .022), and bathing with toilet soap (OR, 0.41; 95% CI, 0.19-0.90; P = .026) appeared to be protective. BUD was not significantly associated with penetrating injuries (P = .14), insect bites near water bodies (P = .84), bacille Calmette-Guerin vaccination (P = .33), or human immunodeficiency virus infection (P = .99). CONCLUSIONS BUD is an environmentally acquired infection strongly associated with exposure to river areas. Exposed skin may facilitate transmission. Until transmission is better defined, control strategies in BUD-endemic areas could include covering exposed skin.

Quality of interhospital transport of critically ill patients: a prospective audit

IntroductionThe aim of transferring a critically ill patient to the intensive care unit (ICU) of a tertiary referral centre is to improve prognosis. The transport itself must be as safe as possible and should not pose additional risks. We performed a prospective audit of the quality of interhospital transports to our university hospital-based medical ICU.MethodsTransfers were undertaken using standard ambulances. On departure and immediately after arrival, the following data were collected: blood pressure, heart rate, body temperature, oxygen saturation, arterial blood gas analysis, serum lactic acid, plasma haemoglobin concentration, blood glucose, mechanical ventilation settings, use of vasopressor/inotropic drugs, and presence of venous and arterial catheters. Ambulance personnel completed forms describing haemodynamic and ventilatory data during transport. Data were collected by our research nurse and analyzed.ResultsA total of 100 consecutive transfers of ICU patients over a 14-month period were evaluated. Sixty-five per cent of patients were mechanically ventilated; 38% were on vasoactive drugs. Thirty-seven per cent exhibited an increased number of vital variables beyond predefined thresholds after transport compared with before transport; 34% had an equal number; and 29% had a lower number of vital variables beyond thresholds after transport. The distance of transport did not correlate with the condition on arrival. Six patients died within 24 hours after arrival; vital variables in these patients were not significantly different from those in patients who survived the first 24 hours. ICU mortality was 27%. Adverse events occurred in 34% of transfers; in 50% of these transports, pretransport recommendations given by the intensivist of our ICU were ignored. Approximately 30% of events may be attributed to technical problems.ConclusionOn aggregate, the quality of transport in our catchment area carried out using standard ambulances appeared to be satisfactory. However, examination of the data in greater detail revealed a number of preventable events. Further improvement must be achieved by better communication between referring and receiving hospitals, and by strict adherence to checklists and to published protocols. Patients transported between ICUs are still critically ill and should be treated as such.

Susceptibility to development of Mycobacterium ulcerans disease: review of possible risk factors

Mycobacterium ulcerans disease, also known as Buruli ulcer (BU), is a disease of subcutaneous fat tissue. BU is prevalent in riverine and swamp areas of the tropical zone in Africa, Asia and South America, and a few scattered foci in Australia. The mode of transmission of M. ulcerans has not been fully elucidated, but inoculation into the subcutaneous tissues probably occurs through penetrating skin trauma. BU has not been linked with HIV infection. Antimycobacterial drug treatment is ineffective, and treatment is surgical. Patients eventually develop scars and contractures, with resulting disabilities, and the disease imposes a large burden on affected populations. The incidence of BU has dramatically increased in West African countries over the last decade. There is an urgent need for research into host and environmental risk factors for BU in order to develop effective strategies to combat this disease. We review possible genetic host susceptibility factors for BU that are relevant in other mycobacterial diseases: natural resistance‐associated macrophage protein‐1 (NRAMP‐1), HLA‐DR, vitamin D3 receptor, mannose binding protein, interferon‐gamma (IFN‐γ) receptor, tumour necrosis factor alpha (TNF‐α), interleukin (IL)‐1α, 1β and their receptor antagonists; and IL‐12. Schistosoma haematobium infection is highly endemic in many BU foci in West Africa, with a striking increase in transmission after river dams were constructed. This observation, and the observations from interaction of schistosomiasis and tuberculosis, have fuelled our hypothesis that schistosomiasis is a risk factor for BU by driving the host immune response towards a predominantly Th‐2 pattern, away from a Th‐1 preponderant protection against mycobacterial infection. If the latter hypothesis is confirmed, enhanced schistosomiasis control should impact on BU.

Mycolactones and Mycobacterium ulcerans disease

CONTEXT Mycobacterium ulcerans causes devastating necrotic lesions in affected individuals. The disease, commonly called Buruli ulcer, is increasing in prevalance in western African countries. Treatment is mainly surgical; no clinical trials have been done to support the use of antimycobacterial drugs. A secreted polyketide toxin, mycolactone, is responsible for the tissue damage; its chemical structure has been elucidated. STARTING POINT Although the main treatment is surgical, many patients with Buruli ulcer present late because of unusual beliefs about the disease and its treatment. Isabelle Aujoulat and colleagues recently showed, in a study in southern Bénin, Africa (Trop Med Int Health 2003; 8: 750-59), that although the ulcer is well recognised, the cause is often seen as environmental or because of witchcraft. In addition, treatment is thought to be destructive, costly, and ineffective. WHERE NEXT? Antimycobacterial drug regimens that hold promise based on animal and preliminary human studies will soon be tested in large well-designed controlled clinical trials. Information gleaned from the genomic sequence of M ulcerans could be used to design more effective vaccines, or new drug targets (eg, that knock out the enzymes of M ulcerans that synthesise mycolactone species).

Paradoxical Responses After Start of Antimicrobial Treatment in Mycobacterium ulcerans Infection

BACKGROUND  Antimicrobial killing in mycobacterial infections may be accompanied by (transient) clinical deterioration, known as paradoxical reaction. To search for patterns reflecting such reactions in the treatment of Buruli ulcer (Mycobacterium ulcerans infection), the evolution of lesions of patients treated with antimicrobials was prospectively assessed. METHODS  The lesion size of participants of the BURULICO antimicrobial trial (with lesions ≤10 cm cross-sectional diameter) was assessed by careful palpation and recorded by serial acetate sheet tracings. Patients were treated with antimicrobials for 8 weeks. For the size analysis, participants whose treatment had failed, had skin grafting, or were coinfected with human immunodeficiency virus were excluded. For every time point, surface area was compared with the previous assessment. A generalized additive mixed model was used to study lesion evolution. Nonulcerative lesions were studied using digital images recording possible subsequent ulceration. RESULTS  Of 151 participants, 134 were included in the lesion size analysis. Peak paradoxical response occurred at week 8; >30% of participants showed an increase in lesion size as compared with the previous (week 6) assessment. Seventy-five of 90 (83%) of nonulcerative lesions ulcerated after start of treatment. Nine participants developed new lesions during or after treatment. All lesions subsequently healed. CONCLUSIONS  After start of antimicrobial treatment for Buruli ulcer, new or progressive ulceration is common before healing sets in. This paradoxical response, most prominent at the end of the 8-week antimicrobial treatment, should not be misinterpreted as failure to respond to treatment. Clinical Trials Registration. ClinicalTrials.gov, NCT00321178.

Early atherosclerosis in systemic sclerosis and its relation to disease or traditional risk factors

IntroductionSeveral systemic autoimmune diseases are associated with an increased prevalence of atherosclerosis which could not be explained by traditional risk factors alone. In systemic sclerosis (SSc), microvascular abnormalities are well recognized. Previous studies have suggested an increased prevalence of macrovascular disease as well. We compared patients with SSc to healthy controls for signs of early atherosclerosis by measuring intima-media thickness (IMT) of the common carotid artery in relation to traditional risk factors and markers of endothelial activation.MethodsForty-nine patients with SSc, of whom 92% had limited cutaneous SSc, and 32 healthy controls were studied. Common carotid IMT was measured by using B-mode ultrasound. Traditional risk factors for cardiovascular disease were assessed and serum markers for endothelial activation were measured.ResultsIn patients with SSc, the mean IMT (median 0.69 mm, interquartile range [IQR] 0.62 to 0.79 mm) was not significantly increased compared with healthy controls (0.68 mm, IQR 0.56 to 0.75 mm; P = 0.067). Also, after correction for the confounders age, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein cholesterol (P = 0.328) or using a different model taking into account the confounders age, HDL cholesterol, and history of macrovascular disease (P = 0.474), no difference in IMT was present between SSc patients and healthy controls. Plaques were found in three patients and not in healthy controls (P = 0.274). In patients, no correlations were found between maximum IMT, disease-related variables, and markers of endothelial activation. Endothelial activation markers were not increased in SSc patients compared with controls.ConclusionSSc is not associated with an increased prevalence of early signs of atherosclerosis.