Safety and tolerability of a single administration of AR-301, a human monoclonal antibody,in ICU patients with severe pneumonia caused by <Emphasis Type="Italic">Staphylococcus aureus</Emphasis>: first-in-human trial

Purpose

Hospital-acquired bacterial pneumonia (HABP) is a critical concern in hospitals with ventilator-associated bacterial pneumonia (VABP) remaining the most common infection in the ICU, often due to Staphylococcus aureus, an increasingly difficult to treat pathogen. Anti-infective monoclonal antibodies (mAb) may provide new, promising treatment options. This randomized, double-blinded, placebo-controlled study aimed at assessing the safety and pharmacokinetics of AR-301, an S. aureus alpha toxin-neutralizing mAb, and exploring its clinical and microbiologic outcomes when used adjunctively with standard-of-care antibiotics.

Methods

Eligibility in this trial required microbiologically confirmed severe S. aureus pneumonia, including HABP, VABP or CABP, treated in the ICU and an APACHE II score ≤?30. Standard-of-care antibiotics selected by the investigators were administered to all patients in the study following clinical and microbiologic confirmation of S. aureus pneumonia. Adjunctive treatment of AR-301 was to start <?36 h after onset of severe pneumonia. AR-301 was administered to four sequentially ascending dose cohorts. The placebo cohort received antibiotics and a placebo buffer. Clinical outcomes were adjudicated by a blinded committee. S. aureus eradication was declared based on a negative follow-up culture and presumed to be negative when no culture was obtained in the presence of clinical improvement.

Results

Thirteen ICUs enrolled 48 patients, with pneumonia attributable to MRSA in six subjects. The study drug displayed a favorable safety profile: Of 343 AEs reported, 8 (2.3%) were deemed related, none serious. In a post hoc subgroup analysis of VABP patients receiving AR-301, ventilation duration was shorter for AR-301-treated patients compared with the placebo group. Overall, there was a trend toward a better and faster microbiologic eradication at day 28. The PK profile of AR-301 is consistent with that of a human IgG1 mAb, with a plasma half-life of about 25 days.

Conclusions

Adjunctive treatment of severe S. aureus HABP with anti-staphylococcal mAbs appears feasible and suggests some clinical benefits, but larger randomized studies are needed to better define its safety and efficacy.

     

Prevalence of intestinal parasites in a population in south of Tehran, Iran

The aim of this study was to describe epidemiologic characteristics of intestinal parasites in a population in south of Tehran, Iran. A retrospective cross-sectional study of patients with suspicious intestinal parasitic infections referred to the Zakaria Razi Laboratory in Shahre-Ray, southern Tehran, Iran, was conducted from April 21, 2004 to October 20, 2005. All stool samples were examined and socio-demographic informations were retrieved. Of 4,371 referred patients, 466 (239 males and 227 females) were laboratory diagnosed with intestinal parasites, with a period prevalence of 10.7%. Blastocystis hominis (B. hominis) and Giardia lamblia (G. lamblia) were the most frequent intestinal parasites. More than half of patients aged (3) 18 years had a low level of educational attainment (e.g. illiterate, primary school, high school) (170/331, 54.1%). Further, majority of patients were homemakers (42.3%, 140/331) or workers (28.1%, 93/331) employed in various business settings such as food industry and construction. Findings of this study showed that intestinal parasitic infections are still a major public health challenge in Iran that needs to be addressed. We believe that public education, improving sanitation conditions of underdeveloped areas/communities, community involvement, and supporting evidence-based practice/programs are the major keys to success in preventing the spread of intestinal parasitic infections in Iran.     

Prevalence of sporadic medullary thyroid carcinoma: the importance of routine measurement of serum calcitonin in the diagnostic evaluation of thyroid nodules

OBJECTIVE The prevalence of sporadic forms of medullary thyroid carcinoma (MTC) has been studied In patients living in an area of moderate iodine deficiency. Such forms of MTC are usually diagnosed after surgery and have little chance of definitive cure. Using the measurement of basal serum calcitonin (CT) levels in a large series of patients with both thyroid disease and normal 24-hour urinary Iodine excretion, we assessed the prevalence of MTC and, in patients affected with the disease, we also evaluated the stage of the disease according to surgical findings and post surgical plasma CT levels. PATIENTS A prospective study of 657 patients with thyroid disease (469 with nodular and 188 with non-nodular thyroid disease). As controls, 40 normal subjects were also studied. MEASUREMENTS In all patients: (1) measurement of basal serum CT, free T4, total T3, TSH levels and serum TSH-receptor, peroxidase and thyroglobulin (Tg) antibody concentrations, (2) thyroid ultrasonography, (3) fine needle aspiration cytology (FNAC). In patients with Increased basal CT levels: (1) measurement of serum CT levels during pentagastrin test prior to surgery, (2) histological examination and immunostaining with both anti-CT and anti-Tg antibodies of all the nodular thyroid tissue surgically removed, (3) measurement of basal and pentagastrin stimulated serum CT values after surgery. RESULTS All the patients with non-nodular thyroid disease had normal basal CT levels. Four patients (0.84%) with nodular thyroid disease (2 with uninodular and 2 with multinodular goitre) had both elevated basal and pentagastrin stimulated CT levels. In the two patients with uninodular goitre, FNAC was suggestive of MTC in 1 (nodular diameter 8.0 cm) and of follicular carcinoma In 1 (nodular diameter 2.5 cm). Histological examination of the nodules confirmed these histotypes. Immunostaining with anti-CT antibodies was positive In the former patient but also In the latter. FNAC was suggestive of benign adenomatous tissues in the two patients with multinodular goitre. Histological examination of all the thyroid nodules confirmed the cytological findings. However, serial sections through the gland in each of these two patients showed an occult follicular carcinoma which had, however, positive staining with anti-CT antibodies. Furthermore, immunostaining with anti-Tg antibodies was negative In the patient with MTC but positive in the 3 patients with follicular carcinoma. Finally, both basal and pentagastrin stimulated CT levels remained elevated after total thyroidectomy only in the patient with FNAC suggesting MTC. CONCLUSIONS This study demonstrates a surprisingly high prevalence of sporadic forms of medullary thyroid carcinoma in patients with nodular thyroid disease. Such forms of medullary thyroid carcinoma seem to be unrelated to iodine intake and may be pure or mixed with a follicular carcinoma. In these mixed thyroid carcinomas, only the neoplastic follicular pattern was seen on both cytological and histological examination. Routine measurements of serum calcitonin levels should therefore be considered an integral part of the diagnostic evaluation of thyroid nodules. Indeed, increasing the accuracy of diagnosis of medullary thyroid carcinoma encourages the surgeon to perform more radical treatment, thus achieving more frequent normalization of post-operative serum calcitonin levels.     

Performance of existing diagnosis/classification criteria for Behcet's disease in Iranian patients: analysis of 5666 patients and 2406 controls

Aim: To analyse the performance of existing diagnosis/classification criteria for Behcet's disease (BD) in Iranian patients. There are 13 sets: Curth (1946), Hewitt (1969), Mason and Barnes (1969), Hewitt revised (1971), Japan (1972), Hubault and Hamza (1974), O'Duffy (1974), Cheng and Zhang (1980), Dilsen (1986), Japan revised (1988), International (1990), Iran (1993), Classification Tree (1993), and Dilsen revised criteria (2000). Methods: All patients from the Behcet's Disease Registry (5666) and control patients (2406) entered the study. Sensitivity, specificity and accuracy were calculated. Results: The most sensitive was Curth criteria with (99.7%), followed by Classification Tree (97.3%), Zhang (93.5%), Iran (91.4%), Japan revised (86.4%), Japan (85.3%), Dilsen (83.7%), Hubault and Hamza (81.6%), Dilsen revised (81.2%), International criteria (79.8%), Hewitt (73.8%), O'Duffy (70.7%), and Masson and Barnes (65.7%). The most specific was Masson and Barnes (99.6%), followed by the International criteria (98.3%), Dilsen revised (98.2%), O'Duffy (97.6%), Japan (97.1%), Japan revised (97%), Classification Tree (96.7%), Hewitt (95.8%), Iran (95.8%), Zhang (92.4%), Dilsen (91.4%), Hubault (90.8%), and Curth (78.6%). The most accurate criteria was Classification Tree (97.1%), followed by Curth (93.4%), Zhang (93.1%), Iran (92.7%), Japan revised (89.6%), Japan (88.8%), Dilsen revised (86.2%), Dilsen (86%), International criteria (85.3%), Hubault (84.3%), Hewitt (80.4%), O'Duffy (78.8%), and Mason and Barnes (75.8%). Discussion: Among the existing criteria, the best to classify Iranian patients is the Classification Tree. The second most accurate is Curth criteria. The difference is statistically significant. Further, Curth criteria is not optimized, having very high sensitivity and low specificity.     

A new radiographic technique for fractures of the orbit and maxilla.

A variant oblique posture of the head is described which eliminates most superimposition in radiographic examination of the orbit and maxilla. The position is simply attained without extraordinary equipment, is comfortable for the patient since there is no pressure on injured parts, and often obviates the need for planigraphy. The following injuries are demonstrated best: displacement at the frontozygomatic suture; deformity of the orbital floor and its distance from the anterior orbital rim; degree of depression of the anterior zygoma, antral wall, and alveolus; and vertical displacement of the zygomatic arch.     

The effects of ranitidine and cimetidine on the pharmacokinetics and pharmacodynamics of metoprolol

The impact of cimetidine, ranitidine and placebo on the pharmacokinetics of metoprolol, given either as a single dose (100 mg) or for 7 days (100 mg b.d.), has been evaluated in two separate studies. The doses used were 800 mg cimetidine daily and 300 mg ranitidine daily. The subjects were all young, healthy volunteers. In the single dose study, cimetidine produced a marked increase in the peak plasma concentration of metoprolol and in the area under the plasma concentration-time curve; ranitidine had less effect, though the area under the curve was significantly greater than placebo. In the chronic dosing study, the area under the curve for metoprolol was also significantly higher on cimetidine (1796 ng h/ml; P less than 0.001) whereas the area under the curve on ranitidine (1258 ng h/ml) was comparable to that on placebo (1183 ng h/ml). Despite these drug-induced changes in plasma metoprolol concentration, neither cimetidine nor ranitidine altered the change in exercise-induced heart rate during dosing with metoprolol.