Efficacy of caspofungin as salvage therapy for invasive aspergillosis compared to standard therapy in a historical cohort.

In a non-comparative study, caspofungin was effective salvage therapy for approximately half of the patients refractory to or intolerant of standard antifungal agents for invasive aspergillosis. To establish a frame of reference for these results, we compared the response to caspofungin with responses to other antifungal agents in a historical cohort of similar patients. The efficacy could be evaluated in 83 patients who received caspofungin 50 mg daily after a 70-mg loading dose. The historical control group, identified through a retrospective review of medical records, included 214 evaluable patients possibly refractory to or intolerant of ≥1 week of standard antifungal therapy. All patients had documented invasive aspergillosis. Favorable response was defined as a complete or partial response to therapy. Underlying diseases, baseline neutropenia, corticosteroid use, and sites of infection were similar in both studies. Most patients had received amphotericin B formulations and/or itraconazole, and were refractory to standard therapy. Favorable response rates were 45% with caspofungin and 16% with standard therapy. The unadjusted odds ratio for a favorable response (caspofungin/standard therapy) was 4.1 (95% confidence interval: 2.2, 7.5). After adjusting for potential imbalances in the frequency of disseminated infection, neutropenia, steroid use, and bone marrow transplantation between groups, the odds ratio remained at 4.1 (2.1, 7.9). Although only tentative conclusions about relative efficacy can be drawn from retrospective comparisons, caspofungin appeared to be at least as efficacious as an amphotericin B formulation and/or itraconazole for the treatment of invasive aspergillosis in patients refractory to or intolerant of their initial antifungal therapy.

Efficacy and safety of caspofungin therapy in elderly patients with proven or suspected invasive fungal infections.

Invasive fungal infections (IFIs) are serious complications in elderly adults. Caspofungin may provide a useful therapeutic option for elderly patients with or at high risk for IFIs. We retrospectively compared efficacy and safety outcomes in elderly (> or = 65 years of age) and non-elderly patients in three clinical trials of caspofungin: a double-blind, randomized trial versus amphotericin B for documented invasive candidiasis (IC); an open-label, non-comparative study of definite or probable invasive aspergillosis (IA); and a double-blind, randomized trial versus liposomal amphotericin B as empirical therapy (ET) in febrile neutropenic patients. A total of 159 elderly patients with a median age of 71 years (range, 65-84) received caspofungin in these studies. The median duration of caspofungin therapy was 12 days for IC and ET, and 28 days for IA. Point estimates for the favorable response rates to caspofungin were numerically higher in elderly versus non-elderly patients with IC (83% vs. 68%) or IA (64% vs. 44%) and were similar in patients receiving ET (36% vs. 34%). Adverse events related to caspofungin occurred in generally similar proportions of elderly versus non-elderly patients with IC (clinical, 33% vs. 27%; laboratory, 17% vs. 29%), with IA (clinical, 7% vs. 13%; laboratory, 13% vs. 14%), or receiving ET (clinical, 47% vs. 47%; laboratory, 24% vs. 22%). Nephrotoxicity and infusion-related toxicity developed in comparable proportions of elderly and non-elderly caspofungin recipients in all three studies. In this post-hoc analysis, caspofungin appeared to be as efficacious and well tolerated in elderly patients as in non-elderly patients.

Efficacy and safety of caspofungin in solid organ transplant recipients.

Efficacy and safety data for the echinocandins in solid organ transplant (SOT) recipients are limited. We reviewed data from three clinical trials that enrolled SOT patients receiving caspofungin therapy for an invasive fungal infection (IFI). Caspofungin was administered at doses ranging from 50 to 100 mg/day. Efficacy was assessed in all patients at the end of caspofungin therapy (EOT). Adverse events (AE) and laboratory data were collected from all patients. We identified data from 22 SOT patients (aged 34-67 years) with proven invasive candidiasis (IC; 6 patients) or proven or probable invasive aspergillosis (IA; 16 patients) who received at least one dose of caspofungin therapy. All patients with IC received caspofungin as primary therapy. Caspofungin success against IC at EOT was 83% (5 of 6), with responses seen across Candida spp. Success by SOT type was: kidney 4 of 5 and liver 1 of 1. All 16 patients with IA (all pulmonary) received caspofungin as salvage therapy. Caspofungin success against IA at EOT was 50% (8 of 16), with responses seen for both definite (3 of 4) and probable IA (5 of 12). Success by SOT type was: heart 2 of 2, heart/lung 0 of 2, kidney 3 of 3, liver 1 of 3, and lung 2 of 6. The outcome was not influenced by caspofungin dose. Caspofungin, dosed for 2 to 162 (mean 36.8) days, was well tolerated. No patient had a serious drug-related adverse event or discontinued caspofungin due to toxicity. Based on these limited data, caspofungin appears to be an effective and well-tolerated option for the treatment of IC and IA in SOT recipients.

Multicenter retrospective development and validation of a clinical prediction rule for nosocomial invasive candidiasis in the intensive care setting.

The study presented here was performed in order to create a rule that identifies subjects at high risk for invasive candidiasis in the intensive care setting. Retrospective review and statistical modelling were carried out on 2,890 patients who stayed at least 4 days in nine hospitals in the USA and Brazil; the overall incidence of invasive candidiasis in this group was 3% (88 cases). The best performing rule was as follows: Any systemic antibiotic (days 1-3) OR presence of a central venous catheter (days 1-3) AND at least TWO of the following-total parenteral nutrition (days 1-3), any dialysis (days 1-3), any major surgery (days -7-0), pancreatitis (days -7-0), any use of steroids (days -7-3), or use of other immunosuppressive agents (days -7-0). The rate of invasive candidiasis among patients meeting the rule was 9.9%, capturing 34% of cases in the units, with the following performance: relative risk 4.36, sensitivity 0.34, specificity 0.90, positive predictive value 0.01, and negative predictive value 0.97. The rule may identify patients at high risk of invasive candidiasis.

Aortic stenosis: the spectrum of practice.

There is significant variation in practice patterns in managing congenital aortic valve stenosis. Review of medical literature reveals no significant information regarding the current practice methods in the treatment of a simple lesion such as aortic stenosis (AS). Therefore, this survey-based study was conducted in an attempt to better understand the uniformity or heterogeneity of practice in treating AS. A questionnaire was prepared to evaluate the style of management of AS. This survey was designed to assess the practice of follow-up visitations, type and frequency of investigative studies, pharmacological therapy, and exercise recommendations. Questions about therapeutic intervention included those of timing and type of intervention. Questionnaires were sent to all academic pediatric cardiology programs in the United States (48 program) and selected international programs from Europe, Asia, and Australasia (19 program). The total number of surveys sent out was 67, and the total number of respondents was 25 (37%), 15 (31%) from the United States and 9 (53%) from outside the United States. The definition of moderate AS varied among respondents. The range provided for mild AS was identified as that with a peak-to-peak pressure gradient of < 25-30 mmHg, peak instantaneous Doppler gradient of < 36-50 mmHg, or mean Doppler gradient of < 25-40 mmHg. On the other hand, severe AS was defined as that with a peak-to-peak gradient of > 50-60 mmHg, peak instantaneous Doppler gradient of > 64-80 mmHg, or mean Doppler gradient of > 45-64 mmHg. In assessing follow-up patterns, 84% of respondents recommended seeing patients with mild AS annually, the longest time of follow-up listed in the questionnaire, whereas 20% suggested follow-up every 6 months. There was no consensus among survey centers regarding follow-up of patients with moderate AS. For severe AS, 16% recommend immediate intervention, 16% arrange follow-up every 6 months, and 56 and 28% recommend follow-up in 3 and 1 month(s), respectively. In making the decision to proceed with biventricular versus univentricular repair in patients with AS in the neonatal period, many factors were considered. Ninety-two percent of respondents rely on mitral valve z score, 84% on aortic valve z score, 52% on left ventricle length, 48% on the presence of antegrade ascending aorta flow, and only 32% considered significant endocardial fibroelastosis as a factor. Rhodes score was used by 20% of respondents in decision making regarding the approach to management of this subset of AS. This study shows that there is consensus in the management of mild and severe forms of AS. As expected, disagreement is present in the definition, evaluation, and therapy of moderate aortic valve stenosis. There is a tendency for catheter intervention except in the presence of dysplastic aortic valve or moderate to severe aortic regurgitation. There is also disagreement regarding methods used to determine biventricular versus univentricular repair of a borderline hypoplastic left heart.

Impact of alternate definitions of fever resolution on the composite endpoint in clinical trials of empirical antifungal therapy for neutropenic patients with persistent fever: analysis of results from the Caspofungin Empirical Therapy Study.

BACKGROUND: Sensitivity analyses were incorporated in a Phase III study of caspofungin vs. liposomal amphotericin B as empirical antifungal therapy for febrile neutropenic patients to determine the impact of varying definitions of fever resolution on response rates. METHODS: The primary analysis used a 5-part composite endpoint: resolution of any baseline invasive fungal infection, no breakthrough invasive fungal infection, survival, no premature discontinuation of study drug, and fever resolution for 48 h during the period of neutropenia. Pre-specified analyses used 3 other definitions for fever resolution: afebrile for 24 h during the period of neutropenia, afebrile at 7 days post therapy, and eliminating fever resolution altogether from the composite endpoint. Patients were stratified on entry by use of antifungal prophylaxis and risk of infection. Allogeneic hematopoietic stem cell transplants or relapsed acute leukemia defined high-risk patients. RESULTS: In the primary analysis, 41% of patients in each treatment group met the fever-resolution criteria. Low-risk patients had shorter durations of neutropenia but failed fever-resolution criteria more often than high-risk patients. In each exploratory analysis, response rates increased in both treatment groups compared to the primary analysis, particularly in low-risk patients. CONCLUSIONS: Response rates for the primary composite endpoint for both treatment groups in this study were driven by low rates of fever resolution. Requiring fever resolution during neutropenia in a composite endpoint can mask more clinically relevant outcomes.

Carney complex presenting with Raynaud's phenomenon and erythematous macules of the extremities.

A 12-year-old male presented with a 6-week history of apparent digital vasculitis with color changes of the distal fingers and erythematous macules of the palms and soles. Physical examination revealed skin findings of Carney complex and an abnormal cardiac examination. Echocardiography demonstrated a large left atrial mass, which caused partial obstruction during diastole and moderate mitral valve insufficiency. Surgical excision and pathological examination of the mass confirmed the presence of a large, peduculated myxoma. This case illustrates the presentation of Carney complex with left atrial myxoma as apparent vasculitis and Raynaud's phenomenon.

Evaluation of biphasic culture system for mycobacterial isolation from the sputum of patients with pulmonary tuberculosis.

Mycobacterial diseases continue to cause high morbidity and mortality. Isolation, identification and sensitivity testing form the backbone of laboratory investigations. M. tuberculosis isolation needs 6-8 weeks on conventional egg containing media. For rapid isolation various methods have been evaluated. We evaluated biphasic system (Middlebrook 7H11 agar slant+Middlebrook 9H broth) in comparison with Lowenstein-Jensen (LJ) medium. In smear positive cases biphasic system showed the recovery rate of 97.05% as against 79.41% on LJ on incubation for 21+/-4.44 and 28+/-3.76 days respectively. In smear negative and culture positive cases biphasic system and LJ showed isolation rates of 91.66% and 66.6% after 36+/-3.44 and 41+/- 4.09 days respectively. Biphasic system showed lower contamination rate (1.33%). Biphasic medium is superior to LJ medium in isolation of M. tuberculosis.

The epidemiology of Kawasaki disease in an urban hospital: does African American race protect against coronary artery aneurysms?

The etiology and pathogenesis of Kawasaki disease (KD) is largely unknown. Certain demographic factors and laboratory findings are predictive of the development of coronary artery (CA) aneurysms. The objectives of this study were to determine the epidemiology of KD patients in an urban hospital and determine risk factors associated with their development of CA abnormalities. A longitudinal case series of KD patients admitted to Children's National Medical Center from 1990 to 2002 was examined. Age, sex, ethnic background, duration of fever prior to diagnosis, address, month diagnosed, and CA abnormalities (ectasia or aneurysms) on echocardiography were recorded. Median household income was obtained from the U.S. Census Bureau Web site. The Student t-test, logistic regression analyses, and the Kruskal-Wallis test were used, with significance assumed at p < 0.05. A total of 302 patients were evaluated. CA abnormalties were found in 27 patients (9%), with aneurysms identified in 13 patients (4%). Age was 2.9 +/- 2.4 years (range, 2 months to 14 years). A total of 51 patients (16%) were < or =1 year and 35 patients (12%) were > or =5 years. Ethnic distribution was 54% (164) African American, 24% (72) Caucasian, 9% (29) Asian/Pacific Islander, 8% (23) Hispanic, and 5% (14) Middle Eastern. Only 2/164 (1.2%) African Americans developed CA aneurysms. Neighborhood median income of the cohort was $45,400 +/- $21,200 ($52,200 +/-$25,800 for patients with aneurysms). A total of 28% of cases clustered between December and January. Cases doubled annually in 1999-2001 compared to 1990-1998 (39 vs 19). Multivariate logistic regression found age between 1 and 5 years [p = 0.045; odds ratio, 0.31; 95% confidence interval (CI), 0.10-0.97] and African American race (p = 0.014; odds ratio, 0.15; 95% CI, 0.03-0.68) to be independently protective against CA aneurysms. Duration of fever prior to diagnosis, considered in 210 patients, was different between patients with and without aneurysms (11 +/- 5.3 vs 6.5 +/- 3.8 days, respectively, p = 0.0007). Multivariate logistic regression found fever longer than 5 days to be the only predictive factor associated with the development of aneurysms and any abnormality. African Americans had a shorter duration of fever than the rest of the cohort (6.03 vs 7.31 days), (p = 0.0087). The epidemiology of KD at our hospital is similar to that at other centers except for the predominance of African Americans with a shorter duration of fever prior to diagnosis and a decreased incidence of CA aneurysms compared to other ethnicities. The protective nature of African American ethnicity against the development of CA aneurysms raises speculation about the role of genetics and its interaction with immunity in the pathogenesis of KD.

Retrospective study of the hepatic safety profile of patients concomitantly treated with caspofungin and cyclosporin A.

BACKGROUND: Mild, transient alanine aminotransferase (ALT) elevations were seen in Phase I studies of caspofungin and cyclosporin A (CsA). METHODS: We conducted a retrospective chart review at four sites to characterize the hepatic safety in patients receiving > or =1 day of both drugs over a 20-month period. Investigators assessed reasons for discontinuing concomitant therapy and the presence/etiology of any hepatotoxicity. RESULTS: Forty patients receiving concomitant therapy for 1-290 days (median 17.5 days) were identified. Although common, liver enzyme abnormalities were frequently attributed to other comorbidities or medications. ALT and/or aspartate aminotransferase (AST) elevations occurred in 14 patients (35%). Five had AST elevations at least possibly related to caspofungin/CsA, but none were >3.6 times the normal upper limit. No ALT elevations were related to caspofungin/CsA. Two of 4 patients had discontinuation of therapy because of hepatotoxicity possibly related to caspofungin/CsA. No serious adverse events occurred because of caspofungin. CONCLUSIONS: These data do not suggest a significant risk of clinically relevant hepatotoxicity with concomitant caspofungin/CsA.

Global distribution and outcomes for Candida species causing invasive candidiasis: results from an international randomized double-blind study of caspofungin versus amphotericin B for the treatment of invasive candidiasis.

In a randomized study, caspofungin was compared with amphotericin B for the treatment of invasive candidiasis in a total of 239 adults from 56 sites in 20 countries. This study provided a unique opportunity to assess the frequency and outcome of invasive candidiasis caused by different Candida species worldwide, and the results are presented here. Efficacy was primarily assessed at the end of intravenous therapy using a modified intent-to-treat (MITT) analysis. This analysis was performed on 224 of the 239 patients enrolled in the study. Attempts were made to collect baseline Candida isolates from all patients for species identification at a central laboratory. Yeasts were identified to the species level using two commercial systems and microscopic examination. Viable baseline isolates were recovered from 210 of the 224 (94%) patients included in the MITT analysis. Candida albicans was the most frequently isolated species in all regions and was responsible for 45% of cases overall. Nevertheless, the majority of cases of infection were caused by non- albicans Candida species. In the USA and Canada, Candida glabrata was the second most commonly isolated pathogen (18%). In contrast, Candida parapsilosis and Candida tropicalis accounted for 55% of cases in Latin America. Outcomes were comparable for patients treated with caspofungin (74% overall; 64% and 80% for infections due to Candida albicans and non- albicans species) and amphotericin B (62% overall; 58% and 68% for infections due to Candida albicans and non- albicans species), and were generally similar across continents. The distribution of Candida species isolated from patients enrolled in a clinical trial may not be representative of pathogens causing invasive candidiasis in the general population. Nevertheless, our findings may affect the regional choice of empirical antifungal therapy for seriously ill patients with suspected or documented invasive candidiasis since different Candida species have varying susceptibility to conventional antifungal drugs.

Telemedicine applications in pediatric cardiology.

Echocardiography is often used to diagnose and exclude important cardiac diagnoses in children. Evolving telemedicine technology has the potential to improve access to echocardiography diagnoses in the intensive care unit, emergency room, and newborn nursery. The two primary modes of telemedicine practice are "store and forward" and "real-time" videoconferencing. A digital echocardiogram (often several one cardiac cycle loops) can be stored at one site and forwarded across a telemedicine network to a receiving station for review at a later time. Pediatric cardiologists often favor "real-time" telemedicine because of the ability to guide sonographers with limited experience in congenital heart disease. A complete telemedicine system requires a modified computer, a low- or high-speed connection, and telemedicine inputs. Several adult and pediatric clinical studies have shown telemedicine to be accurate, improve patient care, be cost-effective, enhance echocardiogram quality and sonographer proficiency, and promote practice expansion. Obstacles to widespread implementation of telemedicine include lack of standardization of telemedicine components, confusing legal issues and licensure requirements, and poor reimbursement.

A case of congenitally protected d-transposition of the great arteries in a very low-birth-weight infant.

An arterial switch is the corrective procedure of choice for d-transposition of the great arteries but may be associated with increased morbidity and mortality when performed in low-birth-weight infants. Conversely, delaying surgery often leads to left ventricular "deconditioning" as pulmonary arteriolar resistance decreases. We present an infant with a birth weight of 940 g with d-transposition of the great arteries with an intact ventricular septum whose bilateral pulmonary artery branch stenosis allowed for maintenance of near systemic left ventricular pressure, thereby protecting against deconditioning. This case also represents the smallest reported patient to undergo a successful balloon atrial septostomy.

Safety and tolerability of caspofungin acetate in the treatment of fungal infections.

Caspofungin acetate is the first member of the novel echinocandin class of antifungal drugs to be marketed in the United States. It has recently been approved for use in patients with invasive aspergillosis who are refractory to or intolerant of conventional therapy. Accordingly, its safety profile is particularly important to review. The safety and tolerability of caspofungin have been examined in 623 persons, including 295 patients who received >/= 50 mg/day for at least one week in clinical studies. In the 263 patients, given caspofungin in randomized double-blind active-control trials to date, there have been no serious clinical or laboratory drug-related adverse events; caspofungin was discontinued in only 2% of these patients because of drug-related adverse experiences. Caspofungin may have potentially important drug interactions with cyclosporine and tacrolimus.

A randomized double-blind study of caspofungin versus amphotericin for the treatment of candidal esophagitis.

Caspofungin is a new broad-spectrum antifungal drug. A multicenter, double-blind, randomized trial was conducted to assess the efficacy, safety, and tolerability of caspofungin relative to amphotericin B in adults with endoscopically documented symptomatic Candida esophagitis. By use of a modified intent-to-treat analysis, endoscopically verified clinical success was achieved in 74% (95% confidence interval [CI], 59%-86%) and 89% (95% CI, 72%-98%) of patients receiving caspofungin at 50 and 70 mg/day, respectively, and in 63% (95% CI, 49%-76%) of patients given amphotericin B at 0.5 mg/kg/day. Therapy was stopped because of drug-related adverse events in 24% of patients in the amphotericin B group and 4% and 7%, respectively, for the caspofungin groups. This report provides the first demonstration of clinical utility for an echinocandin compound. Caspofungin appeared in this study to be as effective as and better tolerated than amphotericin B for the treatment of esophageal candidiasis.

Telecardiology: potential impact on acute care.

Echocardiography is often used to diagnose and exclude important cardiac diagnoses in adults and children. Evolving telemedicine technology has the potential to improve access to echocardiography diagnoses in the intensive care unit, emergency room, and newborn nursery. The two primary modes of telemedicine practice are "store and forward" and "real-time" videoconferencing. A digital echocardiogram (often several one cardiac cycle loops) can be stored at one site and forwarded across a telemedicine network to a receiving station for review at a later time. Pediatric cardiologists often favor "real-time" telemedicine because of the ability to guide sonographers with limited experience in congenital heart disease. A complete telemedicine system requires a modified computer, a low- or high-speed connection, and telemedicine inputs. Several adult and pediatric clinical studies have shown telemedicine to be accurate and cost-effective, improve patient care, enhance echocardiogram quality and sonographer proficiency, and promote practice expansion. Obstacles to widespread implementation of telemedicine include lack of standardization of telemedicine components, confusing legal issues and licensure requirements, and poor reimbursement.