Efficacy of High Doses of Daptomycin versus Alternative Therapies against Experimental Foreign-Body Infection by Methicillin-Resistant Staphylococcus aureus

Since the currently approved dose of daptomycin (6 mg/kg of body weight/day) has been associated with clinical failures and resistance development, higher doses for some difficult-to-treat infections are being proposed. We studied the efficacy of daptomycin at high doses (equivalent to 10 mg/kg/day in humans) and compared it to that of reference and alternative treatments in a model of foreign-body infection with methicillin (meticillin)-resistant Staphylococcus aureus. In vitro studies were conducted with bacteria in the log and stationary phases. For the in vivo model, therapy with daptomycin at 100 mg/kg/day, vancomycin at 50 mg/kg/12 h, rifampin (rifampicin) at 25 mg/kg/12 h, or linezolid at 35 mg/kg/12 h was administered for 7 days. Antibiotic efficacy was evaluated using either bacteria from tissue cage fluids or those attached to coverslips. We screened for the emergence of linezolid- and rifampin-resistant strains and analyzed the surviving population from the daptomycin-treated group. Only daptomycin was bactericidal in both the log- and stationary-phase studies. Daptomycin (decrease in the log number of CFU per milliliter of tissue cage fluid, 2.57) and rifampin (decrease, 2.6 log CFU/ml) were better (P < 0.05) than vancomycin (decrease, 1.1 log CFU/ml) and linezolid (decrease, 0.9 log CFU/ml) in the animal model. Rifampin-resistant strains appeared in 60% of cases, whereas no linezolid resistance emerged. No daptomycin-resistant subpopulations were detected at frequencies of 10⁻⁷ or higher. In conclusion, daptomycin at high doses proved to be as effective as rifampin, and the two were the most active therapies for this experimental foreign-body infection. These high doses ensured a profile of safety from the development of resistance.Daptomycin is a lipopeptide drug with bactericidal activity toward methicillin (meticillin)-resistant Staphylococcus aureus (MRSA) in a concentration-dependent manner (27, 32). It is currently approved for use at 4 mg/kg of body weight/day for skin and soft-tissue infections (1) and at 6 mg/kg/day for bacteremia and right-side endocarditis (12, 14).In recent years, reports of clinical failures and the emergence of resistant strains following daptomycin treatment have raised great concern (6, 18, 31). As a result, higher doses of daptomycin are being proposed as an alternative for some difficult-to-treat infections such as complicated bacteremia and endocarditis. Recently, doses of 10 mg/kg/day were studied using an in vitro model of staphylococcal endocarditis, with the results being promising in terms of efficacy and resistance prevention (25, 26). To date, clinical experience with the activity of the drug at doses higher than 6 mg/kg/day is limited (15, 28), whereas good safety and tolerance profiles for daptomycin at up to 12 mg/kg/day in volunteers have been reported (4).Foreign-body infections are difficult to treat because of the presence of bacterial biofilm and tolerance to antibiotics (10, 39). MRSA is commonly involved in such infections, and daptomycin may be a promising drug (39). However, clinical experience in this area is again scarce, and the recommended doses are not clearly established, there being reports of clinical failures with doses of 4 to 6 mg/kg/day (13, 24).The rat model of tissue cage infection is a well-standardized model that reasonably mimics human device infections (17, 20, 35). In this model, the efficacy of daptomycin has been partially studied (29, 34).Taken together, the available experimental and clinical data seem to indicate that high doses of daptomycin are required in the setting of foreign-body infection.In the present study, we aimed to test the efficacy of daptomycin at doses equivalent to 10 mg/kg/day in humans in a model of foreign-body infection with MRSA, comparing it with the efficacy of the current reference or main alternative treatments such as vancomycin, rifampin (rifampicin), and linezolid. We also sought to analyze the protection offered against the emergence of resistant strains.     

Prevention of surgical site infection by antibiotic spraying in the operative field during cardiac surgery

OBJECTIVE: Despite the many procedures introduced to prevent surgical site infection during cardiothoracic surgery, serious infections still occur. We attempted to reduce surgical site infection by spraying antibiotic solution in the operative field--a procedure since introduced at 4 other Japanese institutions. METHODS: In the latter half of 1990, we began spraying an antibiotic solution of cefazolin (1g) and gentamicin (40 mg)/40 ml of saline placed in a 50 ml syringe and dispensed through an 18 G needle bent at 60 to 80 degrees to clean the wound during surgery. RESULT: No deep surgical site infections or deaths due to infection have occurred among the 502 patients undergoing cardiothoracic surgery under cardiopulmonary bypass at our hospital. This method was used in over 2,100 cases of similar procedures at 4 other institutions. There were 3 deaths due to severe surgical site infection (0.11%). At one institution treating over 1,000 cases a year, the incidence of death due to surgical site infection decreased significantly after this method was introduced. CONCLUSION: These preliminary experiences show that spraying antibiotic solution in the operative field reduces the risk of surgical site infection in cardiothoracic surgery.     

Dermoscopy of solitary angiokeratomas: a morphological study

OBJECTIVES: To describe the dermoscopic structures and patterns associated with solitary angiokeratomas and to determine the sensitivity, specificity, positive predictive value, negative predictive value, and reproducibility of these dermoscopic features. DESIGN: Multicenter retrospective study. SETTING: University hospitals in Spain, Italy, Argentina, New York City, and Austria. PATIENTS: There were 256 patients total, and 32 specimens each of solitary angiokeratomas, melanocytic nevi, Spitz-Reed nevi, malignant melanomas, pigmented basal cell carcinomas, dermatofibromas, seborrheic keratoses, and other vascular lesions (19 angiomas, 7 pyogenic granulomas, 3 spider nevi, 2 lymphangiomas, and 1 venous lake) were consecutively collected from the laboratories of 8 hospitals. Diagnoses of all patients' lesions were confirmed histopathologically. INTERVENTION: Dermoscopic examination. MAIN OUTCOME MEASURES: The frequency, sensitivity, specificity, positive predictive value, negative predictive value, intraobserver agreement, and interobserver agreement of the different dermoscopic features associated with solitary angiokeratomas were calculated, and the differences were evaluated using the chi(2) or Fisher exact test. RESULTS: Six dermoscopic structures were evident in at least 50% of the solitary angiokeratomas: dark lacunae (94%), whitish veil (91%), erythema (69%), peripheral erythema (53%), red lacunae (53%), and hemorrhagic crusts (53%). Dark lacunae exhibited a sensitivity of 93.8% and a specificity of 99.1% (P<.001 for both), not being found in malignant melanomas or pigmented basal cell carcinomas. The positive predictive value was 93.8%, and the negative predictive value was 99.1%. The intraobserver agreement was perfect (kappa, 1.00), and the interobserver agreement was excellent (kappa range, 0.83-1.00) (P<.001 for both). Pattern 1, consisting of dark lacunae and whitish veil, exhibited a sensitivity of 84.4% and a specificity of 99.1% and was not found in malignant melanomas or pigmented basal cell carcinomas. The positive predictive value was 93.1%, the negative predictive value was 97.8%, the intraobserver agreement was perfect (kappa, 1.00), and the interobserver agreement was excellent (kappa range, 0.83-1.00) (P<.001 for all). Conclusion Dermoscopy is helpful in improving the diagnostic accuracy of solitary angiokeratomas and allows the observer to differentiate them from other cutaneous tumors such as malignant melanomas and pigmented basal cell carcinomas.     

LYMPHOCYTIC HYPOPHYSITIS: SPONTANEOUS RESOLUTION ON MRI WITH PROGRESSION OF ENDOCRINE DEFECT

Lymphocytic hypophysitis is an uncommon condition that typically occurs during the last trimester of pregnancy or in the postpartum period. Presentation is of an anterior pituitary mass with varying degrees of pituitary dysfunction. We present a case in which there was dramatic resolution of the pituitary lesion on sequential MRI scanning. Despite this apparent resolution, however, the patient continues to have significant pituitary dysfunction.     

Sustained response after discontinuation of short-and medium-term treatment with eltrombopag in patients with immune thrombocytopenia

Eltrombopag is effective and safe in chronic immune thrombocytopenia (ITP) patients not responding to previous therapy. However, when eltrombopag is discontinued, platelet counts usually return to baseline within 2 weeks. Here, we describe the clinical characteristics of the, to the best of our knowledge, largest case series of patients with ITP, who presented sustained responses after discontinuing eltrombopag (n?=?12). The median time from diagnosis to eltrombopag initiation was 24 months (range, 1–480). The median number of prior therapies was 5 (range, 1–7), and the median duration of eltrombopag treatment was 5 months (range, 1–13). Three patients received eltrombopag for only 1 month. The treatment was well-tolerated. The median (range) follow-up of this case series was of 7 months (6–20), during which all patients maintained a safe platelet count without the need for anti-ITP treatment. The communication of such cases may support the conduction of new studies to investigate which predictive factors could identify ITP patients with sustained responses after discontinuing eltrombopag without additional therapy. The need of long-term use of eltrombopag should be re-examined.