Shimon Kusne

In vitro susceptibilities of 217 clinical isolates of zygomycetes to conventional and new antifungal agents.

ABSTRACT We evaluated the in vitro susceptibilities of 217 zygomycetes to amphotericin B, ketoconazole, fluconazole, itraconazole, voriconazole, posaconazole, caspofungin, and flucytosine. The significant in vitro activity of posaconazole against several species appears to support its reported clinical efficacy. Decreased susceptibility to amphotericin B was noted with Cunninghamella bertholletiae.

Zygomycosis in Solid Organ Transplant Recipients in a Tertiary Transplant Center and Review of the Literature

Zygomycetes are ubiquitous fungi that can cause invasive disease associated with high mortality. We report 10 solid organ transplant recipients with zygomycosis (incidence 2 per 1000) and reviewed 106 cases in the English‐language literature. These included renal (n = 73), heart (n = 16), lung (n = 4), heart/lung (n = 2), liver (n = 19) and kidney/pancreas (n = 2) transplant recipients. All patients were receiving immunosuppression and the vast majority steroids. The clinical presentation included rhino‐sino‐orbital (n = 20), rhinocerebral (n = 16), pulmonary (n = 28), gastrointestinal (n = 13), cutaneous (n = 18), renal (n = 6) and disseminated disease (n = 15). Most frequently isolated genera were Rhizopus (73%) followed by Mucor (13%). The overall mortality was 49%. While rhino‐sino‐orbital disease had the best prognosis, rhinocerebral disease had high mortality (93%) comparable to disseminated disease. A favorable outcome was associated with limited, surgically accessible disease and early surgical intervention along with amphotericin B administration.

Zygomycosis in Solid Organ Transplant Recipients: A Prospective, Matched Case-Control Study to Assess Risks for Disease and Outcome

BACKGROUNDnClinical characteristics, risks, and outcomes in solid organ transplant (SOT) recipients with zygomycosis in the era of modern immunosuppressive and newer antifungal agent use have not been defined.nnnMETHODSnIn a matched case-controlled study, SOT recipients with zygomycosis were prospectively studied. The primary outcome measure was success (complete or partial response) at 90 days.nnnRESULTSnRenal failure (odds ratio [OR], 3.17; P = .010), diabetes mellitus (OR, 8.11; P < .001), and prior voriconazole and/or caspofungin use (OR, 4.41; P = .033) were associated with a higher risk of zygomycosis, whereas tacrolimus (OR, 0.23; P = .002) was associated with a lower risk of zygomycosis. Liver transplant recipients were more likely to have disseminated disease (OR, 5.48; P = .021) and developed zygomycosis earlier after transplantation than did other SOT recipients (median, 0.8 vs 5.7 months; P < .001). Overall the treatment success rate was 60%. Renal failure (OR, 11.3; P = .023) and disseminated disease (OR, 14.6; P = .027) were independently predictive of treatment failure, whereas surgical resection was associated with treatment success (OR, 33.3; P = .003). The success rate with liposomal amphotericin B was 4-fold higher even when controlling for the aforementioned variables.nnnCONCLUSIONSnThe risks identified for zygomycosis and for disseminated disease, including those that were previously unrecognized, have implications for further elucidating the biologic basis and for optimizing outcomes in SOT recipients with zygomycosis.

Variation in antifungal prophylaxis strategies in lung transplantation

Abstract: We conducted a survey of 50 lung transplant centers across the world to evaluate the variation in antifungal prophylaxis practices. These 50 centers performed 63% of the worlds lung transplants reported in 2001. Eighty‐six percent (43/50) of the centers responded to the survey. Sixty‐nine percent (30/43) of centers used universal antifungal prophylaxis. Aerosolized amphotericin B deoxycholate (AmBd) alone or in combination with itraconazole was used at 56% (24/43) of centers. The median duration of prophylaxis with aerosolized AmBd and itraconazole was 30 and 90 days, respectively. Seventy‐four percent of the centers surveyed agreed to participate in future research prophylaxis protocols, which they felt should include both diagnostic and therapeutic arms. Our survey is the first documentation of the international variation in antifungal prophylactic strategies in lung transplant recipients, and underscores the need for multicenter, randomized trials of antifungal prophylaxis in lung transplant recipients.

Clinical Manifestations and Management of Left Ventricular Assist Device–Associated Infections

BACKGROUNDnInfection is a serious complication of left ventricular assist device (LVAD) therapy. Published data regarding LVAD-associated infections (LVADIs) are limited by single-center experiences and use of nonstandardized definitions.nnnMETHODSnWe retrospectively reviewed 247 patients who underwent continuous-flow LVAD implantation from January 2005 to December 2011 at Mayo Clinic campuses in Minnesota, Arizona, and Florida. LVADIs were defined using the International Society for Heart and Lung Transplantation criteria.nnnRESULTSnWe identified 101 episodes of LVADI in 78 patients (32%) from this cohort. Mean age (± standard deviation [SD]) was 57±15 years. The majority (94%) underwent Heartmate II implantation, with 62% LVADs placed as destination therapy. The most common type of LVADIs were driveline infections (47%), followed by bloodstream infections (24% VAD related, and 22% non-VAD related). The most common causative pathogens included gram-positive cocci (45%), predominantly staphylococci, and nosocomial gram-negative bacilli (27%). Almost half (42%) of the patients were managed by chronic suppressive antimicrobial therapy. While 14% of the patients had intraoperative debridement, only 3 underwent complete LVAD removal. The average duration (±SD) of LVAD support was 1.5±1.0 years. At year 2 of follow-up, the cumulative incidence of all-cause mortality was estimated to be 43%.nnnCONCLUSIONnClinical manifestations of LVADI vary on the basis of the type of infection and the causative pathogen. Mortality remained high despite combined medical and surgical intervention and chronic suppressive antimicrobial therapy. Based on clinical experiences, a management algorithm for LVADI is proposed to assist in the decision-making process.

Bacterial, mycobacterial, and protozoal infections after liver transplantation-Part I

Infection is one of the leading causes of morbidity and mortality in liver transplant recipients. More than two-thirds of liver transplant recipients have infection in the first year after transplantation, and infection is the leading cause of death in these patients.1 In addition, release of cytokines during the infection may have other indirect and negative effects, including allograft injury, opportunistic superinfection, and malignancy.1 The risk of infection in liver transplant recipients is determined by the intensity of exposure to infectious agents (hospital or community sources) and the overall immunosuppression level. This “net state of immunosuppression”2 is influenced by the dose, duration, sequence, and choice of immunosuppressive medications, underlying immune deficiencies, the presence of neutropenia or lymphopenia, mucocutaneous barrier integrity, the presence of necrotic tissue, ischemia or fluid collection, metabolic conditions such as diabetes mellitus, and the activity of immunomodulating viruses.2 After solid organ transplantation, there are 3 time periods when specific infections are likely to occur. The patient’s susceptibility to infection during these periods is strongly influenced by surgical factors, the level of immunosuppression and environmental exposure, and the dose, duration, and types of prophylaxis.3,4 Figure 1 depicts an infection time line of typical organisms after solid organ transplantation. During the first period, the month immediately after transplantation, most infections are related to technical or surgical issues and complications. Exposure to infectious agents through prolonged hospitalization before transplantation or during postoperative care may also result in infection. Bacterial and candidal wound infections, urinary infections, catheter-related infections, pneumonias, and Clostridium difficile colitis predominate during this period, and the etiologic organisms are similar to hospital-acquired infections common in other surgical patients.4,5 Although its incidence has markedly diminished with prophylaxis, reactivated human herpesvirus 1 (herpes simplex virus) is also a common viral illness in this time frame. The next period encompasses the second through sixth posttransplant months. During this time, infections from opportunistic organisms predominate as a result of cumulative immunosuppression. Typical infectious organisms of this period include cytomegalovirus, Pneumocystis jiroveci, and Aspergillus species. Other viruses (human herpesvirus 6, hepatitis B and C, human herpesvirus 3 [varicella-zoster virus], and others), fungi (Cryptococcus, Histoplasma, and Coccidioides species), and bacteria (Nocardia species, Listeria species, or Mycobacterium tuberculosis) may also be seen.4 From approximately the seventh to 12th posttransplant months and beyond, most recipients acquire infections such as influenza, urinary tract infections, and community-acquired pneumonias, which are similar to the infections acquired by patients who have not received transplants.4,6,7 Reactivation of human herpesvirus 3 may manifest as herpes zoster, and although it is uncommon, cytomegalovirus infections can occur. Three notable scenarios may enhance patient susceptibility to opportunistic infections, including (1) acute organ rejection necessitating increased immunosuppression therapy, (2) retransplantation, which “restarts” the immunosuppression and infection time line, and (3) chronic viral infections such as human immunodeficiency virus or hepatitis B or C.4 Kusne et al.8 studied 101 consecutive liver transplantation patients for 1 year or longer. The patients received antibiotics for wound prophylaxis for 5 days and nystatin for antifungal prophylaxis for 30 days. No prophylaxis was administered for pneumocystic or viral infections. Figure 2 shows the timing of all severe infections and separately profiles the rates of bacterial, fungal, viral, and protozoal infections. The majority of infections occurred within 6 months of transplantation. Abbreviations: OLT, orthotopic liver transplantation; VRE, vancomycin-resistant enterococci. From the Division of Infectious Diseases, Mayo Clinic, Scottsdale, AZ. Received September 7, 2005; accepted September 13, 2005. Address reprint requests to: Janis E. Blair, MD, Division of Infectious Diseases, Mayo Clinic, 13400 East Shea Blvd., Scottsdale, AZ 85259. Copyright

2016 Infectious Diseases Society of America (IDSA) Clinical Practice Guideline for the Treatment of Coccidioidomycosis

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. Infectious Diseases Society of America considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patients individual circumstances.Coccidioidomycosis, also known as San Joaquin Valley fever, is a systemic infection endemic to parts of the southwestern United States and elsewhere in the Western Hemisphere. Residence in and recent travel to these areas are critical elements for the accurate recognition of patients who develop this infection. In this practice guideline, we have organized our recommendations to address actionable questions concerning the entire spectrum of clinical syndromes. These can range from initial pulmonary infection, which eventually resolves whether or not antifungal therapy is administered, to a variety of pulmonary and extrapulmonary complications. Additional recommendations address management of coccidioidomycosis occurring for special at-risk populations. Finally, preemptive management strategies are outlined in certain at-risk populations and after unintentional laboratory exposure.

Viral and fungal infections after liver transplantation — Part II

Viral and fungal infections in liver transplant recipients are important to recognize and treat early because of their association with substantial morbidity and mortality. Some viruses, such as cytomegalovirus and human herpesvirus 6, have immunomodulatory properties and can facilitate other infections, including fungal infections. Cytomegalovirus has long been recognized as an important virus in transplantation, but in the past decade other viruses have also received attention in the medical literature because of their association with particular clinical syndromes. Although human herpesvirus 6 has been associated with fever, rash, and encephalitis, a direct cause‐and‐effect relationship is still lacking. Human herpesvirus 8 has been found to be the cause of Kaposi sarcoma. Molecular techniques (e.g., pp65 antigenemia and polymerase chain reaction) that have been introduced for routine diagnosis of viruses have facilitated the diagnosis of asymptomatic viral infections and the institution of preemptive therapy. Nonetheless, the diagnosis of invasive fungal infections in liver transplant recipients is often delayed and thus associated with high mortality. Despite the use of new antifungal agents in clinical practice and the reduced incidence of fungal infections because of antifungal prophylaxis regimens, mortality has not decreased. Future patient outcomes may improve with early identification of patients who have risk factors for invasive fungal infections and with the development of new molecular diagnostic techniques for early detection. Liver Transpl 12:2–11, 2006.

Rhino-orbital-cerebral zygomycosis in solid organ transplant recipients

Background. Rhino-orbital-cerebral disease is a significant manifestation of zygomycosis in solid organ transplant (SOT) recipients. However, its characteristics and outcome are not well addressed. Methods. SOT recipients with zygomycosis as per the European Organization for Research and Treatment in Cancer and the Mycoses Study Group criteria in a cohort study at our centers published previously and those identified with a PubMed search from the 1950s to November 2009 were studied. Patients with mycosis involving the sinuses, orbits, or central nervous system (CNS) were included. Results. Patients comprised a total of 90 SOT recipients with rhino-orbital-cerebral zygomycosis, including 13 in our cohort and 77 in the literature. CNS disease occurred in 57% (51 of 90). Overall mortality was 52.3% (46 of 88), and the mortality in patients with CNS disease was 73.5% (36 of 49). In logistic regression analysis, older age (odds ratio [OR] 1.12, 95% confidence interval [CI] 1.04–1.21, P=0.002) was associated with a higher mortality rate, whereas lipid formulations of amphotericin B compared with amphotericin B deoxycholate (OR 0.09, 95% CI 0.02–0.50, P=0.006) and surgery (OR 0.12, 95% CI 0.01–0.94, P=0.043) were independently associated with an improved survival even when controlled for CNS involvement and the era of diagnosis of disease. Conclusions. Rhino-orbital-cerebral zygomycosis, particularly CNS disease, is associated with substantial mortality rate in SOT recipients. Older age is a significant risk factor for mortality, whereas lipid formulations of amphotericin B and surgery improved outcomes.

Treatment of Refractory Coccidioidomycosis With Voriconazole or Posaconazole

BACKGROUNDnCoccidioidomycosis is a fungal infection of the desert southwestern United States. It may be self-limited or may require antifungal therapy. Currently used triazoles (eg, fluconazole and itraconazole) have largely supplanted amphotericin B, which is fraught with adverse effects. Limited case reports and small open-label trials show that voriconazole and posaconazole benefit patients with coccidioidomycosis refractory to first-line agents.nnnMETHODSnWe conducted a retrospective review of patients prescribed voriconazole or posaconazole for coccidioidomycosis at our institution between 1 January 2006 and 1 August 2010. Outcomes were assessed with both a retrospectively applied Mycosis Study Group score (ie, a composite score for symptoms, serology, and radiographic findings) and the documented impressions of treating medical practitioners.nnnRESULTSnTwenty-one patients who received voriconazole and 16 who received posaconazole met study criteria. After a median duration of 6 months of voriconazole treatment, 14 of 21 patients (67%) were improved in overall status, 5 were unchanged, and 2 were unresponsive to voriconazole. After a median of 17 months of posaconazole treatment, 12 of 16 patients (75%) showed improvement, 1 was unchanged, and 3 were unresponsive due to medication intolerance or relapsed infection.nnnCONCLUSIONSnVoriconazole and posaconazole are reasonable but not infallible options for salvage treatment of refractory coccidioidomycosis. Prospective comparative trials are required to provide further insights into their efficacy and utility.