van der Tjipke Werf

Immunomodulatory effects of macrolide antibiotics - part 1: biological mechanisms.

Macrolide antibiotics are well known for their antibacterial and anti-inflammatory properties. This article provides an overview of the biological mechanisms through which macrolides exert this ‘double effect’. Their antibacterial effect consists of the inhibition of bacterial protein synthesis, impaired bacterial biofilm synthesis, and the attenuation of other bacterial virulence factors. Apart from these direct antimicrobial effects, macrolides are known for their modulating effect on many components of the human immune system. By influencing the production of cytokines, they have a dampening effect on the proinflammatory response. Furthermore, the majority of cells involved in the immune response are, in one way or another, influenced when macrolide antibiotics are administered. Having such an obvious effect on the various aspects of the immune system, macrolides seem to be exceptionally suited for the treatment of chronic inflammatory diseases.

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.

Dog-bite induced sepsis : a report of four cases

Occasionally, a dog-bite is complicated by a systemic overwhelming infection. We report four consecutive patients who were admitted to our intensive care unit because of sepsis syndrome following dog-bites. The history of these patients did not reveal any immunocompromising conditions. Capnocytophaga canimorsus (C. canimorsus) was cultured from the blood culture of 2 patients. Our data illustrate that in patients with lack of immune-deficiency severe sepsis may develop.

Systemic and local interferon-gamma production following Mycobacterium ulcerans infection

Buruli ulcer disease (BUD) is an emerging predominantly tropical disease caused by Mycobacterium ulcerans. The initial pre‐ulcerative skin lesion often breaks down into an ulcer with undermined edges. Healing is common but may require considerable time, and scarring often results in functional limitations. Considerable evidence has now emerged that patients with early BUD cannot mount a sufficient protective T helper 1 (Th1) cell response to M.u2003ulcerans, but uncertainty remains as to whether immune protection is restored over time. This study investigates the Th1 cell response of patients with various stages of BUD on mycobacterial antigens. We measured interferon (IFN)‐γ levels after ex vivo whole blood stimulation with tuberculin purified protein derivative (PPD), and compared the Th1 cell response of individuals with pre‐ulcerative, ulcerative and healed BUD as well as healthy controls. Moreover, the systemic Th1 cell response was related to histopathological features in the various stages of surgically resected BUD lesions. We show that patients with ulcerative and healed BUD produce significantly higher IFN‐γ levels after mycobacterial ex vivo whole blood stimulation than healthy controls, and that patients with a granulomatous tissue response produce higher IFN‐γ levels than individuals without. We therefore suggest that the mounted Th1 cell response in ulcerative BUD patients might be related to their histopathological tissue response.

Late recurrence of Wegener's granulomatosis presenting as solitary upper lobe pulmonary mass

Recurrent Wegeners granulomatosis (WG) was diagnosed in a 40 year old man presenting with a solitary mass in the right lung apex and with possible lymph node enlargement in the anterior mediastinum, resembling malignancy. Eight years previously, a first episode of WG involving the upper airways and kidneys, but not the lungs, had been successfully treated with prednisolone and cyclophosphamide, which could be stopped after 2 yrs. The antineutrophil cytoplasmic antibody titres (anti-protease 3), which had been very high during the first disease episode, failed to predict the recurrence.

Prone position in a spontaneously breathing near-drowning patient

Sir: In 1977 Douglas et al. [1] first observed improvement in arterial oxygen tension (PaO2) by prone positioning that prevented the need for mechanical ventilation in a patient with acute lung injury. Now, we describe a second case with moderate respiratory insufficiency where managing the spontaneously breathing patient in the prone position avoided the need for endotracheal intubation and mechanical ventilation. A 16-year-old boy with a history of epilepsy was admitted to hospital with acute, moderate respiratory insufficiency resulting from near drowning after a generalized seizure. On examination his temperature was 37.5 C and blood pressure 130/ 80 mmHg. He was slightly confused, there were spontaneous movements of the extremities and idiomuscular reflexes were present. Cardiac and abdominal examination revealed no specific abnormalities. He presented with tachypnea and mild cough and produced frothy blood-tinged sputum. His respiration rate varied between 30 and 40 breaths/min. Oxygen was applied through a face mask [approximate fractional inspired oxygen (FIO2) of 0.40]. On auscultation, crackles were noted over the left lung. Moderate respiratory insufficiency was based on the clinical symptoms and the PaO2/FIO2 was 31 kPa (233 mmHg). In order to improve gas exchange and reduce the work of breathing in our patient, we considered continuous positive airway pressure by face mask, but we first tried the prone position. The positional change was well tolerated and resulted in a remarkable clinical recovery with improved oxygenation: PaO2 rose from 12.5 to 22 kPa, arterial carbondioxide tension from 5.7 to 6.0 kPa, and the alveolar-arterial oxygen difference changed from 17.8 kPa (134 mmHg) to 4.1 kPa (33.2 mmHg) within 2 h. As a result, the high fractional inspired oxygen was tapered down. Chest radiograph in the supine position showed left unilateral consolidations (Fig.1a). On the chest radiographs (taken in the supine position) after 3 and 20 h of prone position, the pulmonary abnormalities had resolved (Figs.1b and 1c). The patient made an uneventful recovery, mechanical ventilation was redundant and he was discharged from hospital on day 4. While there seems to be little doubt of the beneficial effects of prone position on oxygenation in mechanically ventilated patients with the acute respiratory distress syndrome (ARDS) [2,3], it remains unclear whether the same holds true in moderate respiratory insufficiency. In our patient, prone positioning rapidly reversed hypoxemia and prevented the necessity of orotracheal intubation and mechanical ventilation. Prone position alters the transpulmonary pressure in the atelectatic dorsal lung regions with a reduction in VA/Q mismatch and shunt [4]. The observed improvement in the alveolar-arterial oxygen difference coincided with favorable changes in radiographic appearance when the patient was turned from the supine to the prone position. Whether the changes in transpulmonary pressure due to maneuvering the body position of our patient are of an order of magnitude sufficient to open consolidated pulmonary units has often been suggested but is still questioned [5]. Perhaps the overall improvement in aeration observed in our patient is an additive Intensive Care Med (1999) 25: 1469±1478 Ó Springer-Verlag 1999 CORRESPONDENCE

Non-conventional mechanical ventilation in severe ARDS, illustrated by a complicated case

When conventional respiratory strategies fail to maintain adequate oxygenation treatment of severe ARDS is largely empirical. Modern techniques such as inverse ratio ventilation, permissive hypercapnia, NO inhalation and lowering tidal volumes/pressures are advocated. We report on a patient with severe ARDS who showed all the complications of the disease. The risks and benefits of (non)conventional ventilatory strategies are discussed and illustrated.

Cefpirome and continuous venovenous hemofiltration

Sir: The initial dosing of antimicrobial treatment in sepsis should clearly be high enough to achieve blood and tissue levels well above the minimal inhibitory concentration of the target micro-organisms. Obviously, the initial loading dose does not depend on elimination impairment, but rather on the apparent volume of distribution (VD). Gomez et al. [1] found that VD in another cephalosporin, ceftazidime, is higher in septic patients than in healthy volunteers. In the relatively mild systemic inflammatory response syndrome after trauma Jacolot et al. [2] found no significant difference in VD of cefpirome between patients (0.29 l/kg) and healthy controls (0.26 l/kg) while in our study VD was slightly higher in septic patients(0.33 l/kg). In several of the published studies addressing the pharmacokinetics of antimicrobials in sepsis and renal failure, plasma drug concentrations show wide distributions, which can conceivably be explained by varying degrees of severity of sepsis. Initial antimicrobial underdosing, not overdosing, is the important pitfall in these patients with sepsis and multiple organ failure, and their renal failure with continuous venovenous hemofiltration (CVVH) should have no bearing on initial loading doses. With continued renal replacement therapy, however, drug elimination may vary widely, especially if the antimicrobial drug studied has very low plasma binding, as is the case with cefpirome. We studied the areal-lifeo situation in our hospital, in which filter change is sometimes delayed by several hours, while filter dysfunction usually precedes breakdown as a result of clotting. Thalhammers group [3] have used highflux membranes with a considerably higher hemofiltration clearance: 2.5 times higher than that our system. Joos et al. [4] have compared predicted drug elimination from creatinine clearance with measured drug elimination in 12 antimicrobial products in a group of 24 patients treated with CVVH and found a good correlation. Our study confirmed the sieving coefficient of cefpirome, with ultrafiltration rate being 15 ml/ min and using the same filter type predicted by Phillips et al. [5], but the recommendation of course related only to the setting described. The study of pharmacokinetics in CVVH typically aims at preventing dangerous underand overdosing, and it is critically important that such studies are repeated in different clinical settings. Individual intensivists should design their own treatment protocols based on a critical appraisal of published studies in which patients with similar pathologies are included, and similar treatment modalities are employed as in their own patient population. Antimicrobial prescriptions are often started in the ICU based on the clinical suspicion of infection. If no micro-organisms are cultured, and if the clinical condition of the patient has improved after few days, stopping of antimicrobial treatment should be an important consideration. Toxicity from overdosing is one concern, but continued antimicrobial pressure, especially in subtherapeutic blood and tissue concentrations, is another major concern, because of the inherent threat of induction of antimicrobial resistance.

Failure of Sengstaken balloon tamponade for rebleeding after tissue adhesive injection in a fundic varix

A 61-year-old man developed a huge fundic varix due to portal hypertension in alcoholic liver cirrhosis. After a third injection therapy session with tissue adhesive (Histoacryl) massive hemorrhage developed. Sengstaken (gastric) balloon tamponade failed. Autopsy showed a huge, solid varix with a large hole on its side, inaccessible with the Sengstaken balloon.