False-positive hepatitis C virus serology after placement of a ventricular assistance device.

BACKGROUND: Ventricular assist devices (VADs) have been associated with immune activation and sensitization. We observed several cases of false-positive (FP) hepatitis C virus (HCV) antibody (Ab) tests in patients being evaluated for orthotopic heart transplant (OHT), prompting us to investigate this further. METHODS: We reviewed all VAD and OHT cases at Johns Hopkins from 2005 to 2012. FP HCV serology was defined as an equivocal or low-positive HCV Ab, plus either (i) a negative recombinant immunoblot (RIBA) and/or HCV nucleic acid test (NAT), or (ii) an indeterminate RIBA and negative NAT. RESULTS: In 53 patients with available HCV testing, nearly 40% of patients (21/53: 39.6%) developed FP HCV Ab tests after VAD placement: 4 patients had negative NAT, 12 had negative RIBA, and 5 had an indeterminate RIBA and negative NAT. All patients with indeterminate RIBA tests had isolated reactivity to the same HCV protein, c100p/5-1-1p (NS4b protein). In 3 of 4 VAD patients who had OHT and repeat HCV Ab testing after VAD removal, repeat HCV Ab was negative (699-947 days after OHT); in 1 case, FP HCV serology persisted (5 days after OHT). Thirteen patients had OHT alone and none developed a FP HCV Ab. CONCLUSIONS: FP HCV Ab results following VAD placement are very common. Reversal of FP serology in several patients after VAD removal is suggestive of a possible association with the VAD hardware. Clinicians should be aware of this phenomenon, as it could lead to delays in determining eligibility for OHT and increased costs.

Voriconazole therapeutic drug monitoring: results of a prematurely discontinued randomized multicenter trial.

BACKGROUND: Voriconazole (VOR) levels are highly variable, with potential implications to both efficacy and safety. We hypothesized that VOR therapeutic drug monitoring (TDM) will decrease the incidence of treatment failures and adverse events (AEs). METHODS: We initiated a prospective, randomized, non-blinded multicenter study to compare clinical outcomes in adult patients randomized to standard dosing (clinician-driven) vs. TDM (doses adjusted based on levels). VOR trough levels were obtained on day 5, 14, 28, and 42 (or at completion of drug; ± 3 days). Real-time dose adjustments were made to maintain a range between 1-5 µg/mL on the TDM-arm, while levels were assessed retrospectively in the standard-arm. Patient questionnaires were administered to assess subjective AEs. RESULTS: The study was discontinued prematurely, after 29 patients were enrolled. Seventeen (58.6%) patients experienced 38 AEs: visual changes (22/38, 57.9%), neurological symptoms (13/38, 34.2%), and liver abnormalities (3/38, 7.9%). VOR was discontinued in 7 (25%) patients because of an AE (4 standard-arm, 3 TDM-arm). VOR levels were frequently out of range in the standard-arm (8 tests >5 µg/mL; 9 tests <1 µg/mL). Three dose changes occurred in the TDM-arm for VOR levels <1 µg/mL. Levels decreased over time in the standard-arm, with mean VOR levels lower at end of therapy compared to TDM (1.3 vs. 4.6 µg/mL, P = 0.008). CONCLUSIONS: VOR TDM has become widespread clinical practice, based on known variability in drug levels, which impaired accrual in this study. Although comparative conclusions are limited, observations of variability and waning levels over time support TDM.

Endemic fungal infections in solid organ and hematopoietic cell transplant recipients enrolled in the Transplant-Associated Infection Surveillance Network (TRANSNET).

BACKGROUND: Invasive fungal infections are a major cause of morbidity and mortality among solid organ transplant (SOT) and hematopoietic cell transplant (HCT) recipients, but few data have been reported on the epidemiology of endemic fungal infections in these populations. METHODS: Fifteen institutions belonging to the Transplant-Associated Infection Surveillance Network prospectively enrolled SOT and HCT recipients with histoplasmosis, blastomycosis, or coccidioidomycosis occurring between March 2001 and March 2006. RESULTS: A total of 70 patients (64 SOT recipients and 6 HCT recipients) had infection with an endemic mycosis, including 52 with histoplasmosis, 9 with blastomycosis, and 9 with coccidioidomycosis. The 12-month cumulative incidence rate among SOT recipients for histoplasmosis was 0.102%. Occurrence of infection was bimodal; 28 (40%) infections occurred in the first 6 months post transplantation, and 24 (34%) occurred between 2 and 11 years post transplantation. Three patients were documented to have acquired infection from the donor organ. Seven SOT recipients with histoplasmosis and 3 with coccidioidomycosis died (16%); no HCT recipient died. CONCLUSIONS: This 5-year multicenter prospective surveillance study found that endemic mycoses occur uncommonly in SOT and HCT recipients, and that the period at risk extends for years after transplantation.

Isavuconazole activity against Aspergillus lentulus, Neosartorya udagawae, and Cryptococcus gattii, emerging fungal pathogens with reduced azole susceptibility.

Isavuconazole is an extended-spectrum triazole with in vitro activity against a wide variety of fungal pathogens. Clinical isolates of molds Aspergillus lentulus and Neosartorya udagawae and yeast Cryptococcus gattii VGII (implicated in the outbreak in the Pacific Northwest, North America) exhibit reduced susceptibilities to several azoles but higher susceptibilities to isavuconazole.

Histoplasmosis and subcutaneous nodules in a kidney transplant recipient: erythema nodosum versus fungal panniculitis.

Erythema nodosum (EN)-like lesions are a rare occurrence after solid organ transplantation. Differential diagnosis includes infective panniculitis, which can be a feature of progressive disseminated histoplasmosis (PDH), an uncommon but severe form affecting primarily immunocompromised hosts. We report on a fatal case of PDH, which presented as fungal panniculitis masquerading as EN in a renal allograft recipient 25 years after transplantation. We discuss the clinical, histopathological, and microbiological characteristics of this rare complication, with focus on its distinction from EN. This case emphasizes the central role of biopsy in transplant recipients presenting with cutaneous lesions, and the importance of clinicopathologic correlation and complementary microbiological investigations.

Epidemiology, outcomes, and mortality predictors of invasive mold infections among transplant recipients: a 10-year, single-center experience.

BACKGROUND: The epidemiology of invasive mold infections (IMI) in transplant recipients differs based on geography, hosts, preventative strategies, and methods of diagnosis. METHODS: We conducted a retrospective observational study to evaluate the epidemiology of proven and probable IMI, using prior definitions, among all adult hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) recipients in the era of "classic" culture-based diagnostics (2000-2009). Epidemiology was evaluated before and after an initiative was begun to increase bronchoscopy in HSCT recipients after 2005. RESULTS: In total, 106 patients with one IMI were identified. Invasive aspergillosis (IA) was the most common IMI (69; 65.1%), followed by mucormycosis (9; 8.5%). The overall rate of IMI (and IA) was 3.5% (2.5%) in allogeneic HSCT recipients. The overall incidence for IMI among lung, kidney, liver, and heart transplant recipients was 49, 2, 11, and 10 per 1000 person-years, respectively. The observed rate of IMI among human leukocyte antigen-matched unrelated and haploidentical HSCT recipients increased from 0.6% annually to 3.0% after bronchoscopy initiation (P < 0.05). The 12-week mortality among allogeneic HSCT, liver, kidney, heart, and lung recipients with IMI was 52.4%, 47.1%, 27.8%, 16.7%, and 9.5%, respectively. Among allogeneic HSCT (odds ratio [OR]: 0.07, P = 0.007) and SOT (OR: 0.22, P = 0.05) recipients with IA, normal platelet count was associated with improved survival. Male gender (OR: 14.4, P = 0.007) and elevated bilirubin (OR: 5.7, P = 0.04) were significant predictors of mortality for allogeneic HSCT and SOT recipients with IA, respectively. CONCLUSIONS: During the era of culture-based diagnostics, observed rates of IMI were low among all transplants except lung transplant recipients, with relatively higher mortality rates. Diagnostic aggressiveness and host variables impact the reported incidence and outcome of IMI and likely account for institutional variability in multicenter studies. Definitions to standardize diagnoses among SOT recipients are needed.

Donor-derived organ transplant transmission of coccidioidomycosis.

Coccidioidomycosis in solid organ transplant recipients most often occurs as a result of primary infection or reactivation of latent infection. Herein, we report a series of cases of transplant-related transmission of coccidioidomycosis from a single donor from a non-endemic region whose organs were transplanted to 5 different recipients. In all, 3 of the 5 recipients developed evidence of Coccidioides infection, 2 of whom had disseminated disease. The degree of T-cell immunosuppression and timing of antifungal therapy initiation likely contributed to development of disease and disease severity in these recipients. This case series highlights the importance of having a high index of suspicion for Coccidioides infection in solid organ transplant recipients, even if the donor does not have known exposure, given the difficulties of obtaining a detailed and accurate travel history from next-of-kin.

Rapidly progressive cutaneous Rhizopus microsporus infection presenting as Fournier's gangrene in a patient with acute myelogenous leukemia.

Members of the genus Rhizopus within the class Zygomycetes can cause devastating opportunistic infections. Cutaneous disease arising from direct inoculation of fungal spores has the potential to disseminate widely. Here, we describe a dramatic case of cutaneous Rhizopus infection involving the penis in a patient with acute myelogenous leukemia. Despite aggressive surgical debridement, systemic antifungal therapy, and donor lymphocyte infusion, the infection was ultimately fatal. This case illustrates the unique diagnostic and therapeutic challenges in the clinical management of cutaneous Rhizopus infection.

Neosartorya udagawae (Aspergillus udagawae), an emerging agent of aspergillosis: how different is it from Aspergillus fumigatus?

A recent report on several cases of invasive aspergillosis caused by Neosartorya udagawae suggested distinctive patterns of disease progression between N. udagawae and Aspergillus fumigatus. This prompted us to characterize N. udagawae in comparison to A. fumigatus. Our findings showed that both species exist in two mating types at similar ratios and produce gliotoxin. However, the thermotolerance of the two species differs: while A. fumigatus is able to grow at 55 degrees C but not at 10 degrees C, N. udagawae is able to grow at 10 degrees C but fails to grow at >42 degrees C. Furthermore, compared to A. fumigatus, the conidia of N. udagawae require longer incubation periods to germinate at 37 degrees C and are more susceptible to neutrophil attack as well as hydrogen peroxide; N. udagawae is also less virulent in gp91(phox-/-) mice. These findings suggest that growth and susceptibility to the host response might account for the reduced virulence of N. udagawae and the subtle distinction in the progression of the disease caused by the two species.

Epidemiology and outcome of invasive fungal infections in solid organ transplant recipients.

Contemporary epidemiology and outcomes of invasive fungal infections (IFIs) in solid organ transplant (SOT) recipients are not well described. From March 2004 through September 2007, proven and probable IFIs were prospectively identified in 17 transplant centers in the United States. A total 429 adult SOT recipients with 515 IFIs were identified; 362 patients received a single and 67 patients received >or=2 organs. Most IFIs were caused by Candida species (59.0%), followed by Aspergillus species (24.8%), Cryptococcus species (7.0%), and other molds (5.8%). Invasive candidiasis (IC) was the most frequently observed IFI in all groups, except for lung recipients where invasive aspergillosis (IA) was the most common IFI (P<0.0001). Almost half of IC cases in liver, heart, and lung transplant recipients occurred during the first 100 days post transplant. Over half of IA cases in lung recipients occurred >1 year post transplant. Overall 12-week mortality was 29.6%; liver recipients had the highest mortality (P=0.05). Organ damage, neutropenia, and administration of corticosteroids were predictors of death. These results extend our knowledge on the epidemiology of IFI in SOT recipients, emphasizing the occurrence of IC early after non-lung transplant, and late complications with molds after lung transplant. Overall survival appears to have improved compared with historical reports.

Using routine blood parameters to anticipate clinical outcomes in invasive aspergillosis.

OBJECTIVE: In invasive aspergillosis (IA), monitoring response to antifungal treatment is challenging. We aimed to explore if routine blood parameters help to anticipate outcomes following IA. METHODS: Post hoc secondary analysis of two multicenter randomized trials was performed. The Global Comparative Aspergillosis Study (GCA, n = 123) and the Combination Antifungal Study (CAS, n = 251) constituted the discovery and validation cohorts respectively. The outcome measures were response to treatment and survival to 12 weeks. Interval platelet, galactomannan index (GMI) and C-reactive protein (CRP) levels prior and during antifungal treatment were analysed using logistic regression, Kaplan-Meier survival and receiver operating characteristic (ROC) analyses. RESULTS: The 12-week survival was 70.7% and 63.7% for the GCA and CAS cohorts respectively. In the GCA cohort, every 10 × 109/L platelet count increase at week 2 and 4 improved 12-week survival odds by 6-18% (odds ratio (OR) 1.06-1.18, 95% confidence interval (CI) 1.02-1.33). Survival odds also improved 13% with every 10 mg/dL CRP drop at week 1 and 2 (OR 0.87, 95% CI 0.78-0.97). In the CAS cohort, week 2 platelet count was also associated with 12-week survival with 10% improved odds for every 10 × 109/L platelet increase (OR, 1.10, 95% CI 1.04-1.15). A GMI drop of 0.1 unit was additionally found to increase the odds of treatment response by 3% at the baseline of week 0 (OR 0.97, 95% CI 0.95-0.99). Week 2 platelet and CRP levels performed better than GMI on ROC analyses for survival (area under ROC curve 0.76, 0.87 and 0.67 respectively). A baseline platelet count higher than 30 × 109/L clearly identified patients with >75% survival probability. CONCLUSIONS: Higher serial platelets were associated with overall survival while GMI trends were linked to IA treatment response. Routine and simple laboratory indices may aid follow-up of response in IA patients.

Central nervous system involvement in cryptococcal infection in individuals after solid organ transplantation or with AIDS.

BACKGROUND: Cryptococcus neoformans is an important pathogen of immunocompromised hosts. Manifestations of cryptococcal infection have not been compared between populations based on the nature of the underlying immune deficiencies. METHODS: The Prospective Antifungal Therapy Alliance (PATH) is a registry that collects clinical data from patients with invasive fungal infections from medical centers in North America. Univariate analyses and group comparisons were conducted from the PATH registry for cases of infection due to Cryptococcus species occurring between March 2004 and April 2008. RESULTS: A total 235 cases of proven infection due to Cryptococcus species were documented, all of which were due to C. neoformans (52 in solid organ transplant [SOT] recipients, 107 in patients infected with the human immunodeficiency virus [HIV], and 76 with neither HIV nor organ transplantation). A total of 140 cases manifested as meningitis (25 in SOT recipients, 88 in HIV-positive patients, and 27 in those with neither risk factor). Of individuals with cryptococcal infection, 44.2% of SOT recipients had central nervous system (CNS) disease, while 84.1% of those with HIV infection presented with CNS involvement (P=0.0265). SOT recipients receiving calcineurin inhibitors (CNIs) were less likely to have CNS involvement in cryptococcal infection (40.1% versus 66.7%). Overall, 12-week mortality for patients with cryptococcal infection in the PATH Alliance registry was 22.6% (21.2% for SOT, 15.9% for HIV-infected patients, and 32.9% for patients with risk factors other than HIV infection or organ transplantation). CONCLUSIONS: In a prospectively assembled cohort of individuals with proven infection due to C. neoformans, CNS involvement was more common in individuals with HIV infection than in SOT recipients. The role of CNIs in the reduction of risk for CNS cryptococcosis remains to be defined. Overall survival of patients with cryptococcal infection in immunocompromised hosts has improved over time. Observed differences in the context of various host immune deficits provide a basis for further investigation of cryptococcosis and other opportunistic infections.

Micafungin alone or in combination with other systemic antifungal therapies in hematopoietic stem cell transplant recipients with invasive aspergillosis.

We describe herein 98 hematopoietic stem cell transplant (HSCT) recipients with invasive aspergillosis (IA) (refractory in 83) who received micafungin either alone (8 patients) or in combination with other licensed antifungal therapies (OLAT) (90 patients). Of the 8 monotherapy patients, 4 were failing OLAT, received de novo micafungin, or were intolerant to prior OLAT (2 patients each). Of the 90 patients treated with combination, 7 had de novo IA and 83 had refractory infection. Most patients (81) had pulmonary IA, 42 (43%) had graft-versus-host disease (GVHD), and 26 (27%) were neutropenic (absolute neutrophil count <500 cells/mm(3)) at onset of treatment. Successful response was seen in 25/98 (26%); an additional 12 patients achieved stable disease. Response was seen in 2/9 (22%) in de novo treatment, 21/87 (24%) in refractory patients, and 2/2 (100%) in toxicity failure patients. Additionally, response was seen in 22 of the 90 (24%) patients treated with combination therapy, and in 3 of 8 (38%) patients who were treated with micafungin alone. No significant differences in responses were found based on type of HSCT, GVHD status, site of IA, or Aspergillus species, and no significant toxicity was seen. Micafungin was well tolerated, even at high doses, and is a reasonable option for treatment of IA in this high-risk patient population.

Comparison of three methodologies for the determination of pulmonary fungal burden in experimental murine aspergillosis.

Quantitative culture, quantitative PCR and the galactomannan enzyme immunoassay (EIA) were compared for their ability to determine the pulmonary fungal burden in a murine model of invasive aspergillosis. Quantitative culture of specimens containing hyphae under-represented the absolute fungal burden in established infection when compared with the two other methods. The best correlation was observed between the two non-culture methods. Higher variability was observed with the galactomannan EIA when compared with quantitative PCR. Collectively, these data suggest that quantitative PCR is the preferred method for determination of the pulmonary fungal burden in experimental aspergillosis.

Regulatory Pathways for New Antimicrobial Agents: Trade-offs to Keep the Perfect From Being the Enemy of the Good.

In 2002, Shlaes and Moellering warned that pharmaceutical companies were abandoning antibiotic research and development due to changing regulatory standards regarding noninferiority (NI) clinical trials. NI trials are subject to unique biases that may yield false-positive conclusions. The US Food and Drug Administration (FDA) developed guidance to ensure that NI results truly reflect drug efficacy. These changes, intended to reduce uncertainty in trial results, have shaped trial enrollment and conduct in ways that now require reflection.

Prospective analysis of Staphylococcus aureus bacteremia in nonneutropenic adults with malignancy.

PURPOSE: To determine the primary sources and secondary complications of Staphylococcus aureus bacteremia (SAB) in cancer patients, as well as predictors of outcome in cancer patients with SAB. PATIENTS AND METHODS: Fifty-two patients at Duke University Medical Center met entry criteria between September 1994 and December 1996 for this prospective cohort study involving hospitalized nonneutropenic adult cancer patients with SAB. All subjects were observed throughout initial hospitalization and were evaluated again at 6 and 12 weeks or until death. RESULTS: SAB was intravascular device-related in 42%, tissue infection-related (TIR) in 44%, and unidentifiable focus-related (UFR) in 13%. Seventeen patients (33%) were found to have metastatic infections or conditions, with eight (15%) developing infectious endocarditis (IE). Patients with TIR bacteremia were less likely than other patients to develop IE (4% v 24%, P =.06). The overall mortality rate was 38%, the SAB-related mortality rate was 15%, and the rate of SAB relapse was 12%. Methicillin resistance was not associated with adverse outcome. Inability to identify a point of entry (UFR bacteremia), however, was associated with a higher overall mortality rate (100% v 24%, P =.0006). Furthermore, a 72-hour surveillance blood culture positive for organisms was associated with an increased incidence of IE (P =.0006), metastatic infections or conditions (P =.0002), SAB relapse (P =.038), and SAB-related death (P =.038). CONCLUSION: SAB in cancer patients is associated with significant morbidity from frequent metastatic infections or conditions including IE, as well as considerable mortality. Unknown initial infection site and 72-hour surveillance cultures positive for organisms were predictive of a complicated course and poor final outcome.

Role of echocardiography in evaluation of patients with Staphylococcus aureus bacteremia: experience in 103 patients.

OBJECTIVES: The purpose of this prospective study was to examine the role of echocardiography in patients with Staphylococcus aureus bacteremia (SAB). BACKGROUND: The reported incidence of infective endocarditis (IE) among patients with SAB varies widely. Distinguishing patients with uncomplicated bacteremia from those with IE is therapeutically and prognostically important, but often difficult. METHODS: One hundred-three consecutive patients undergoing both transthoracic (TTE) echocardiography and transesophageal (TEE) echocardiography were prospectively evaluated. All patients presented with fever and > or = 1 positive blood culture and were followed up for 12 weeks. RESULTS: Although predisposing heart disease was present in 42 patients (41%), clinical evidence of infective endocarditis (IE) was rare (7%). TTE revealed anatomic abnormalities in 33 patients, but vegetations in only 7 (7%), and was considered indeterminate in 19 (18%). TEE identified vegetations in 22 patients (aortic valve in 5, mitral valve in 9, tricuspid valve in 4, catheter in 2 and pacemaker in 2, abscesses in 2, valve perforation in 1 and new severe regurgitation in 1; 26 total [25%]). Using Duke criteria for the diagnosis of IE, definite IE was present in 26 patients (25%). Clinical findings and predisposing heart disease did not distinguish between patients with and without IE. The sensitivity of TTE for detecting IE was 32%, and the specificity was 100%. The addition of TEE increased the sensitivity to 100%, but resulted in one false positive result (specificity 99%). TEE detected evidence of IE in 19% of patients with a negative TTE and 21% of patients with an indeterminate TTE. At follow-up, cure of staphylococcal infection occurred in a similar percentage of patients with and without IE (77% and 75%, respectively). However, death due to sepsis was significantly more likely among patients with IE (4 of 26 [15%]) than among those without IE (2 of 77 [3%]) (p = 0.03). CONCLUSIONS: Our results suggest that IE is common among patients admitted to the hospital with SAB and is associated with an increased risk of death due to sepsis. TEE is essential to establish the diagnosis and to detect associated complications. Therefore, the test should be considered part of the early evaluation of patients with SAB.

Staphylococcus aureus bacteremia in the surgical patient: a prospective analysis of 73 postoperative patients who developed Staphylococcus aureus bacteremia at a tertiary care facility.

BACKGROUND: Staphylococcus aureus is a frequent cause of infection and bacteremia in the postoperative patient. Unfortunately, there have been no prospective studies evaluating these patients, so the incidence of complications, subsequent treatment algorithms, and prognosis remain undefined. The objectives of this prospective study of postoperative Staphylococcus aureus bacteremia (SAB) were to define the primary sources of bacteremia and to identify the common complications of SAB in the postoperative setting. METHODS: A registry was developed into which 309 consecutive adult patients with SAB were prospectively enrolled between September 1994 and December 1996. Seventy-three of these patients (23.6%) developed SAB in the postoperative setting. RESULTS: Analysis of the clinical features of these 73 postoperative patients revealed three important results. First, infective endocarditis is surprisingly common in postoperative patients with SAB and the classical stigmata of endocarditis are often absent. Transesophageal echocardiography was performed in 31 of 73 patients; 10 of these patients (32.3%) met Duke Criteria for definite endocarditis, but only 3 of these patients had vegetations detected by transthoracic echocardiography, and only 2 patients had peripheral stigmata of infective endocarditis. Second, the development of SAB after cardiothoracic surgery was strongly associated with underlying S. aureus mediastinitis. Twenty-one of the 23 patients who developed SAB after median sternotomy had mediastinitis (positive predictive value 91.3%). In many cases, the diagnosis of mediastinitis was not apparent when SAB was detected. Third, complications, relapses, and mortality were high in postoperative patients with SAB. Fourteen of 73 patients (19.2%) developed multiple noncardiac metastatic complications, including metastatic abscesses (5), septic emboli (3), pneumonia or empyema (2), septic arthritis (1), epidural abscess (1), and other metastatic foci (7). Twelve of 73 patients (16.4%) had recurrent staphylococcal infection after treatment of their first episode of SAB, including 8 patients (11.0%) with recurrent bacteremia. Of patients who survived, those with recurrent staphylococcal infection were more likely to have an infected surgical wound than were patients who were cured of infection (p = 0.05). Finally, mortality attributable to SAB (11.0%), and all-cause mortality (21.9%), was high. CONCLUSIONS: SAB in the postoperative setting is often a severe disease with high morbidity and mortality. A thorough diagnostic evaluation is indicated in surgical patients with S. aureus bacteremia to ensure the early detection of metastatic infections such as infective endocarditis and to define foci such as mediastinitis re quiring surgical intervention.

Antifungal prophylaxis in hematopoietic stem cell transplant recipients.

Efforts at preventing and treating fungal infection in hematopoietic stem cell transplant (HSCT) recipients must take into account the types of infections likely to be encountered during the different risk periods in hosts with different underlying risks. Given the emergence of molds as prevalent pathogens and the long duration of risk in allogeneic HSCT recipients, optimal antifungal prophylaxis would consist of treatment that can be given over a prolonged period and that would provide both anti-Candida and anti-Aspergillus activity. Optimal empiric therapy would consist of a broad-spectrum agent in the absence of more sensitive and specific methods for microbial diagnosis. Fluconazole (Diflucan) is currently the standard prophylactic agent for candidiasis, although mold-active agents and alternative strategies for polyene administration are being investigated. The gold standardfor empiric therapy is currently a polyene antifungal, yet an increased appreciation for amphotericin B-resistant yeasts and molds, and less toxic mold-active alternatives, might lead to the use of other compounds in the future. The recent development of multiple alternatives emphasizes our need to establish treatment algorithms that consider both the likely pathogens and potential toxicities.

Agonist-induced adherence of equine neutrophils to fibronectin- and serum-coated plastic is CD18 dependent.

Adherence to vascular endothelium and extracellular matrix proteins is a pre-requisite for neutrophil accumulation at sites of inflammation. In this study, equine neutrophil adherence to fibronectin and autologous serum-coated plastic in response to PAF, hrIL-8, hrC5a and PMA has been measured. In addition, the mechanisms involved have been investigated using monoclonal antibodies (MoAbs) against the beta2 integrin CD18. PAF and hrC5a caused similar, concentration dependent, increases in adherence to fibronectin- and serum-coated plastic (maximum responses 19 +/- 4% and 19 +/- 3% for PAF and 15 +/- 4% and 16 +/- 2% for hrC5a on fibronectin- and serum-coated plastic, respectively). Adherence in response to PMA, although not reaching a maximum over the time course studied, was of a similar magnitude on the two surfaces (41 +/- 1% and 38 +/- 2% with 10(-7) M PMA on fibronectin- and serum-coated plastic, respectively). In contrast, the maximum adherence caused by hrIL-8 was significantly lower on fibronectin- than on serum-coated plastic (9 +/- 3% vs. 17 +/- 2%; 10(8) x M hrIL-8). Pre-incubation with MoAbs against CD18 (H20A and 6.5E) caused concentration related inhibition of stimulus-induced adherence to both fibronectin- and serum-coated plastic. Equine neutrophil adherence in response to PAF, hrIL-8, hrC5a and PMA therefore appears to be mediated by a CD18 dependent mechanism.