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.

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.

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.

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.

Case report: pulmonary vein stenosis following RF ablation of paroxysmal atrial fibrillation: successful treatment with balloon dilation.

Paroxysmal atrial fibrillation and atrial tachycardia may originate from a focal source in one or multiple pulmonary veins. A focal origin facilitates a potential cure amendable to radiofrequency ablation. Herein we report the case of a 16 year old adolescent male with a tachycardia induced cardiomyopathy who presented with very frequent paroxysmal episodes of atrial fibrillation, atrial flutter and atrial tachycardia. The origin of the arrhythmia was mapped to the secondary branches of the left lower pulmonary vein using an octapolar micro-mapping catheter. Immediately following application of three radiofrequency lesions, angiography of the left lower pulmonary vein revealed a region of focal stenosis at the site of energy application, with delayed pulmonary venous emptying. Attempts to relieve any element of spasm using direct administration of nitroglycerin were unsuccessful. Three months later repeat catheterization revealed an unchanged region of tight anatomical stenosis. Balloon dilation of two stenotic areas resulted in dramatic relief of the obstruction and improved venous drainage. Recatheterization 6 months later revealed mild restenosis that was successfully redilated. Intracardiac ultrasound demonstrated focal constriction. Care should be exercised in attempting RF ablation in distal arborization sites of the pulmonary veins in children, because of the small caliber compared to adult subjects. Radiofrequency induced focal areas of stenosis may be amenable to balloon catheter dilation.

Impact of prolonged waiting times of neonates awaiting heart transplantation.

OBJECTIVES: This study analyzed waiting times and outcomes of neonates listed for heart transplantation at two medical centers from 1991 through 1994. STUDY DESIGN: Retrospective analysis was performed to examine waiting times, charges, morbidity, and outcomes. RESULTS: Of the 30 neonates listed for transplantation, 15 received hearts, with 10 late survivors. Waiting time increased from 25 +/- 8 days in 1991 and 1992 to 58 +/- 7 days in 1993 and 1994 (p < 0.01), and the hospital charge per patient increased from $118,300 +/- $31,500 to $198,700 +/- $25,400 (p < 0.05). Freedom from sepsis predicted receiving heart transplantation (p < 0.01). Lack of a preoperative central intravenous catheter, no preoperative mechanical ventilation, and A-negative blood type predicted heart transplantation survival (p < 0.05). The chances of receiving and surviving transplantation were the same in the two periods. There was a trend toward greater morbidity among neonates waiting more than 35 days. CONCLUSIONS: Waiting times and charges have increased significantly over the last 4 years. Patients who are free of sepsis, lack a preoperative central intravenous catheter, are not mechanically ventilated preoperatively, and have A-negative blood type have better outcomes.

The role of molecular techniques in the understanding of emerging infections.

Emerging infections are defined as infections that are newly identified or recognized, or those whose incidence in humans has significantly increased over the past 20 years. The interaction of several factors contributes to the emergence of infectious disease, including changes in human behavior, technological advances, economic development, increased international travel, microbial adaptation and lapses in public health measures. Biomedical research has allowed us to identify and classify previously uncultured pathogens, characterize microbial virulence factors, create new diagnostic tests and develop vaccines. Here, we highlight a few emerging infections and illustrate the role that molecular medicine has played in furthering our understanding of these diseases.

Intravenous ribavirin by constant infusion for serious influenza and parainfluenzavirus infection.

Three patients with severe lower respiratory tract influenza or parainfluenzavirus infections were treated with continuous ribavirin infusion, given as a 5 mg/kg/hour (h) loading infusion for 8 h followed by 1.5 mg/kg/h for 2 to 6 days. This regimen was generally well tolerated. Plasma ribavirin concentrations were 40 to 60 microM in two patients during the continuous infusion phase and lower concentrations were detectable in tracheobronchial secretions. In temporal association with ribavirin administration, viral shedding diminished in one patient and ceased in two patients, one of whom had developed virus resistant to amantadine. The strategy of continuous ribavirin infusion warrants controlled testing for its antiviral and possible clinical effectiveness.

Orthomyxoviral and paramyxoviral infections in transplant patients.

In summary, orthomyxo- and paramyxoviruses cause clinically important infections in transplant patients. Patients often develop lower respiratory tract involvement and sometimes respiratory failure, which almost is uniformly fatal. Bone marrow transplant recipients appear to be at higher risk of severe disease than are solid-organ recipients, but well defined criteria to predict those patients who will be severely affected are not available. Factors associated with more severe disease include the type of viral pathogen, with pneumonia occurring more commonly with RSV and PIV infection, and the degree of immunosuppression of the patient, particularly the pre-engraftment phase in bone marrow transplant recipients. Because mortality is associated with development of pneumonia, prompt diagnosis and studies for concurrent infections are essential. Evaluation of fever and upper respiratory tract symptoms in patients in the peritransplant period should include sampling of nasopharyngeal and throat for virus isolation and antigen detection for respiratory viruses. If patients develop lower respiratory tract symptoms, early bronchoscopy with BAL is indicated. No specific antiviral therapy has proved effective in the treatment of established respiratory viral infections of transplant patients. Aerosolized ribavirin or, in the instance of influenza A virus infection, oral rimantadine might be considered as early therapy to prevent severe lower respiratory disease. Intravenous ribavirin, currently available on a compassionate use basis, might be considered for treating measles virus infection. In patients with lower tract disease due to RSV, the addition of immunoglobulin with high neutralizing antibody titers to RSV or intravenous ribavirin are additional considerations to forestall respiratory failure. Controlled studies of these interventions are needed in transplant patients before their use can be recommended routinely.

Indications for echocardiography in the diagnosis of infective endocarditis in children.

The role of transthoracic echocardiography as a diagnostic tool in children suspected of having infective endocarditis (IE) has not been defined. We hypothesized that echocardiography is only useful in children in whom there is high clinical suspicion of IE based on physical examination findings or persistently positive blood cultures. Echocardiographic reports and medical records of all inpatients (n = 133) from 1990 to 1992 who underwent echocardiography for suspected IE were reviewed. Fifty-nine of the 133 patients (44%) identified had either persistently positive blood cultures (n = 48), physical examination findings of IE (n = 20), or both (n = 9). The echocardiogram was positive in 7 of these patients (12%) and negative in all 74 patients without positive physical findings or positive blood cultures (p = 0.003). A new or changing precordial murmur, embolic phenomena, congestive heart failure, mechanical ventilation, and positive blood cultures were predictive of positive echocardiograms for IE by univariate analysis. The presence of fever, immune deficiency, and central lines, alone or in combination, was not predictive of a positive echocardiogram. In the absence of physical findings or persistently positive blood cultures, echocardiography is a low-yield study and is unlikely to aid in the diagnosis of IE in children.

Fluoroquinolones: how to use (but not overuse) these antibiotics.

The fluoroquinolone antibiotics are relatively new agents with long serum half lives, a high degree of bioavailability, and a broad spectrum of activity against many gram-negative and some gram-positive organisms. They are useful in a range of clinical settings but should not be considered as first-line treatment of many infections. Specific indications include chronic osteomyelitis caused by multiple-resistant gram-negative bacilli, chronic bacterial prostatitis refractory to other oral antibiotics, complicated urinary tract infections, and empiric therapy of suspected bacterial GI infections. Quinolones may also be considered when patients are allergic to a conventional agent, when infections are caused by multiple-resistant gram-negative bacilli, or when the toxicity of an alternate therapy is greater.

A controlled trial of scheduled replacement of central venous and pulmonary-artery catheters.

BACKGROUND: The incidence of infection increases with the prolonged use of central vascular catheters, but it is unclear whether changing catheters every three days, as some recommend, will reduce the rate of infection, It is also unclear whether it is safer to change a catheter over a guide wire or insert it at a new site. METHODS: We conducted a controlled trial in adult patients in intensive care units who required central venous or pulmonary-artery catheters for more than three days. Patients were assigned randomly to undergo one of four methods of catheter exchange: replacement every three days either by insertion at a new site (group 1) or by exchange over a guide wire (group 2), or replacement when clinically indicated either by insertion at a new site (group 3) or by exchange over a guide wire (group 4). RESULTS: Of the 160 patients, 5 percent had catheter-related bloodstream infections, 16 percent had catheters that became colonized, and 9 percent had major mechanical complications. The incidence rates (per 1000 days of catheter use) of bloodstream infection were 3 in group 1, 6 in group 2, 2 in group 3, and 3 in group 4; the incidence rates of mechanical complications were 14, 4, 8, and 3, respectively. Patients randomly assigned to guide-wire-assisted exchange were more likely to have bloodstream infection after the first three days of catheterization (6 percent vs. 0, P = 0.06). Insertions at new sites were associated with more mechanical complications (5 percent vs. 1 percent, P = 0.005). CONCLUSIONS: Routine replacement of central vascular catheters every three days does not prevent infection. Exchanging catheters with the use of a guide wire increases the risk of bloodstream infection, but replacement involving insertion of catheters at new sites increases the risk of mechanical complications.

Pharmacologic interventions aimed at preventing the biologic effects of endotoxin.

In summary, an increased understanding of the pathogenesis and pathophysiology of septic shock has led to the development and evaluation of potential adjunctive therapies. Although several agents show promise in certain experimental settings, definitive recommendations regarding the use of these agents are not yet possible. Although several therapies have shown benefit when the subject receives treatment prior to the onset of sepsis, most have had varying degrees of success following the development of septicemia.