Aspergillus calidoustus case series and review of the literature.

Aspergillus calidoustus, previously classified as Aspergillus ustus, is an emerging pathogen in immunocompromised persons. We describe four recent cases of A. calidoustus and review 37 additional cases of A. calidoustus (n = 8) or A. ustus (n = 29) published through June 2016. Twenty (49%) cases occurred in patients with hematologic malignancy and/or receipt of hematopoietic cell transplantation, and 13 (32%) occurred in solid organ transplant recipients. Antifungal susceptibility was reported in 49% of cases and in 42% treatment failed. Overall mortality was 66% and, where reported, attributable mortality was 30%. A. calidoustus infection is associated with a high mortality rate and frequently displays in vitro antifungal resistance.

Treatment of MDR urinary tract infections with oral fosfomycin: a retrospective analysis.

OBJECTIVES: Limited options for treating MDR organisms have led clinicians to turn to older antimicrobial agents that may display activity against such infections. One such agent is fosfomycin, an oral drug with activity against a variety of Gram-positive and -negative bacteria, but only approved for use in the USA for urinary tract infection (UTI) due to Escherichia coli and Enterococcus faecalis. The purpose of this study was to assess the efficacy of fosfomycin treatment of MDR UTI and identify predictors of outcome. PATIENTS AND METHODS: A retrospective review was performed of patients treated for MDR UTI at a large quaternary medical centre between 1 January 2010 and 30 September 2014. Sixty patients received 69 courses of fosfomycin in the inpatient or outpatient setting for UTIs due to Enterobacteriaceae, Pseudomonas aeruginosa or VRE. RESULTS: In the 58 patients for whom follow-up data were available, the treatment success rate (no persistent or recurrent infection) was 55%. Chronic kidney disease was associated with persistent infection (OR = 3.56, 95% CI = 1.02-12.40, P = 0.04). No other factors, including comorbidities, infecting organism, fosfomycin MIC or number of doses of fosfomycin received, were associated with recurrent infection or treatment failure. CONCLUSIONS: This study supports the use of fosfomycin as an oral option for treating MDR UTIs. Additional studies are required to assess the optimal dosing and utility of combination therapy to decrease the incidence of treatment failure.

Herpesvirus Respiratory Infections in Immunocompromised Patients: Epidemiology, Management, and Outcomes.

Among immunocompromised individuals, members of the human Herpesviridae family are frequently encountered pathogens. Cytomegalovirus, herpes simplex virus 1 and 2, varicella zoster virus, Epstein-Barr virus, and human herpesvirus-6, -7, and -8 all establish latency after infection and can reactivate during periods of immunosuppression, leading to both direct and indirect adverse effects on the host including severe organ dysfunction as well as allograft rejection and loss after transplantation. While not all herpesviruses are primary respiratory pathogens, many of their manifestations include involvement of the respiratory tract. This article discusses the individual viruses, their epidemiology, and clinical manifestations as well as recommended treatment and preventive strategies.

Acinetobacter baumannii infection in solid organ transplant recipients.

INTRODUCTION: Acinetobacter baumannii can cause serious infection in susceptible patients, but little has been published regarding risk factors for infection and outcomes in solid organ transplant (SOT) recipients. METHODS: We identified A. baumannii infection among adult SOT recipients that occurred between January 2001 and March 31, 2008 at a Chicago transplant center and evaluated characteristics of these infections and outcomes. RESULTS: Thirty-three individuals developed A. baumannii infection during the study period. Seventy-nine percent had healthcare-associated infection with respiratory tract as the most common site of infection (64%). Eighty-two percent of patients had received antibiotics within two wk prior to A. baumannii infection and multidrug resistance (MDR) or extensive resistance (XDR) occurred in 85%. The median time to onset of infection was five months after transplant. The 30-d mortality was 24% and was associated with XDR. Administration of an appropriate antibiotic within three d was associated with lower 30-d mortality (OR 0.16, p = 0.047). All isolates tested against colistin were susceptible. CONCLUSION: SOT recipients with A. baumannii infection had high mortality associated with delay in appropriate antibiotic therapy and XDR organisms. The use of colistin-containing treatment regimens should be considered in these patients when A. baumannii infection is suspected or identified in patients who have received prior antibiotics.

Posaconazole: Use in the Prophylaxis and Treatment of Fungal Infections.

Posaconazole, a fluorinated triazole antifungal drug, is approved by the U.S. Food and Drug Administration (FDA) for (1) prophylaxis against Aspergillus and Candida infections in immunocompromised patients at high risk for these infections and (2) oropharyngeal candidiasis (OPC), including cases refractory to fluconazole and/or itraconazole. The European Medicines Agency (EMA) has approved posaconazole for (1) treatment of aspergillosis, fusariosis, chromoblastomycosis, and coccidioidomycosis in patients who are refractory to or intolerant of other azoles or amphotericin B; (2) first-line therapy for OPC for severe disease or in those unlikely to respond to topical therapy; and (3) prophylaxis of invasive fungal infections in high-risk hematologic patients and stem cell transplant recipients. In addition to approved indications, posaconazole has been used with success as salvage therapy for invasive mold infections and endemic mycoses in patients who are refractory to or intolerant of other antifungal agents, and as prophylaxis or salvage therapy in children, for whom indications are more limited owing to a paucity of data. Posaconazole has potent in vitro activity against a broad range of fungi and molds, including Aspergillus, Candida, Cryptococcus, filamentous fungi, and endemic mycoses including coccidioidomycosis, histoplasmosis, and blastomycosis. Importantly, posaconazole is much more active than other azoles against many Mucorales species and the combination of posaconazole with other antifungal agents may be synergistic. Hence, posaconazole is a potential candidate as a single or combination agent for difficult-to-treat fungal infections. Posaconazole has an excellent safety profile; to date, serious side effects are rare, even with prolonged use. However, newer posaconazole formulations achieve higher blood levels and it remains to be seen whether this may lead to an increase in the rate of adverse effects. Currently, posaconazole is used predominantly for prophylaxis and salvage therapy of fungal infections in adults. Indications for use as initial therapy of fungal infections and for broader use in children will depend on the accrual of additional clinical data.

The risk of seizures among the carbapenems: a meta-analysis.

OBJECTIVES: A consensus exists among clinicians that imipenem/cilastatin is the most epileptogenic carbapenem, despite inconsistencies in the literature. METHODS: We conducted a meta-analysis of all randomized controlled trials comparing carbapenems with each other or with non-carbapenem antibiotics to assess the risk of seizures for imipenem, meropenem, ertapenem and doripenem. RESULTS: In the risk difference (RD) analysis, there were increased patients with seizure (2 per 1000 persons, 95% CI 0.001, 0.004) among recipients of carbapenems versus non-carbapenem antibiotics. This difference was largely attributed to imipenem as its use was associated with an additional 4 patients per 1000 with seizure (95% CI 0.002, 0.007) compared with non-carbapenem antibiotics, whereas none of the other carbapenems was associated with increased seizure. Similarly, in the pooled OR analysis, carbapenems were associated with a significant increase in the risk of seizures relative to non-carbapenem comparator antibiotics (OR 1.87, 95% CI 1.35, 2.59). The ORs for risk of seizures from imipenem, meropenem, ertapenem and doripenem compared with other antibiotics were 3.50 (95% CI 2.23, 5.49), 1.04 (95% CI 0.61, 1.77), 1.32 (95% CI 0.22, 7.74) and 0.44 (95% CI 0.13, 1.53), respectively. In studies directly comparing imipenem and meropenem, there was no difference in epileptogenicity in either RD or pooled OR analyses. CONCLUSIONS: The absolute risk of seizures with carbapenems was low, albeit higher than with non-carbapenem antibiotics. Although imipenem was more epileptogenic than non-carbapenem antibiotics, there was no statistically significant difference in the imipenem versus meropenem head-to-head comparison.

The significance of cytomegalovirus viremia at day 100 or more following allogeneic hematopoietic stem cell transplantation.

We conducted a single-center retrospective review of patients who had received allogeneic hematopoietic stem cell transplantation (HSCT) between January 2003 and December 2007, to assess the incidence and risk factors for late CMV infection and evaluate its effects on outcomes. Twenty of 49 HSCT recipients (41%) developed CMV infection at day ≥ 100 after transplant. Univariable analysis showed that having a matched unrelated donor, having early CMV infection, having a diagnosis of lymphoma, and receipt of antithymocyte globulin were risks for developing late CMV. On multivariable analysis, the occurrence of CMV prior to day 100 and lymphoma conferred a significant risk for late CMV infection. Of the 20 patients with late CMV infection, two patients manifested CMV disease (10%). Despite the relatively low incidence of CMV disease, patients with late CMV infection had a 4.8-fold increased risk of death compared to patients without late CMV. Identifying patients at increased risk for developing late CMV infection may be important for prompting more intensive monitoring of infection late after HSCT, particularly because this manifestation of CMV is associated with poorer outcomes.

Alternative agents to vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infections.

Resistant gram-positive infections, specifically methicillin-resistant Staphylococcus aureus (MRSA), carry an increased risk for morbidity and mortality. Historically, MRSA has been a cause of nosocomial infections, although recent reports have noted an increased prevalence in community-acquired MRSA infections. Vancomycin is the preferred agent to treat MRSA. However, cases of S. aureus with reduced susceptibility to vancomycin have been reported, prompting the need for alternative treatment options. In this review, we discuss the currently available agents with MRSA activity and those in development. Linezolid and quinupristin/dalfopristin have been demonstrated as effective although potential toxicities must be taken into consideration before their use. Daptomycin, tigecycline, telavancin, and ceftaroline are well tolerated but lack the clinical data to support a superior place in treatment over vancomycin. Several new agents in various stages of development have also demonstrated MRSA activity. Currently, vancomycin remains the gold-standard treatment option for MRSA infections. In situations that limit its use, consideration of patient-specific parameters, cost, and relevant clinical data demonstrating drug safety and efficacy should be employed for the selection of the appropriate alternative agent.

Timing of susceptibility-based antifungal drug administration in patients with Candida bloodstream infection: correlation with outcomes.

OBJECTIVES: We sought to determine the impact of timing of appropriate antifungal therapy, as assessed by susceptibility results, on patient survival. METHODS: Patients ≥16 years of age with first episodes of candidaemia during 2001-09 were included. Clinical data were collected retrospectively, including time to appropriate antifungal therapy and patient survival. RESULTS: The study population included 446 patients [243 (54%) female, mean age 53 years] with candidaemia, 380 (85%) of whom had antifungal susceptibility data. Candida albicans was the most common pathogen (221, 50%) followed by Candida glabrata (99, 22%), Candida parapsilosis (59, 13%), Candida tropicalis (48, 11%) and Candida krusei (6, 1%). Appropriate antifungal therapy consisted of fluconazole (177, 40%), an echinocandin (125, 28%), amphotericin B (41, 9%) and voriconazole (6, 1%); 97 (22%) failed to receive appropriate antifungal therapy. The 30 day mortality was 34% (151/446) and there was no clear relationship between time from positive culture to receipt of appropriate antifungal therapy and 30 day survival. On multivariable Cox regression, increased APACHE II score [hazard ratio (HR) 1.11, 95% CI 1.09-1.13, P<0.001], cirrhosis (HR 2.15, 95% CI 1.48-3.13, P<0.001) and HIV infection (HR 2.03, 95% CI 1.11-3.72, P=0.02) were independent predictors of mortality. A secondary analysis requiring patients in the early treatment group to have received ≥24 h of effective antifungal therapy did show a significant mortality benefit to receiving antifungal treatment within 72 h of a positive blood culture being drawn (30 day mortality for early treatment: 27% versus 40%, P=0.004; HR for mortality with delayed treatment on multivariable analysis: 1.41, 95% CI 1.01-1.98, P=0.045). CONCLUSIONS: Candida bloodstream infection is associated with high mortality, despite timely receipt of appropriate antifungal therapy.

Rapid development of Acinetobacter baumannii resistance to tigecycline.

A 53-year-old woman experienced a multidrug-resistant (MDR) Acinetobacter baumannii urinary tract infection 5 months after undergoing kidney and liver transplantation. The tigecycline minimum inhibitory concentration (MIC) for her A. baumannii isolate was 1.5 microg/ml; the patient received 2 weeks of therapy with intravenous tigecycline as a 100-mg loading dose followed by 50 mg every 12 hours, with no lapses in treatment and with resolution of the infection. Three weeks later, MDR A. baumannii was isolated from her sputum in the setting of clinical evidence of pneumonia, and tigecycline was restarted; the tigecycline MIC for the A. baumannii isolate was 2 microg/ml. At approximately the same time, the patient was found to have a paraspinal abscess and spinal osteomyelitis. Cultures of the abscess fluid grew A. baumannii with a tigecycline MIC of 24 microg/ml. A follow-up sputum culture again yielded A. baumannii, but with a tigecycline MIC of 24 microg/ml. Urine culture at that time also grew A. baumannii with a tigecycline MIC of 24 microg/ml. Clinicians should be aware that tigecycline MICs for A. baumannii isolates may increase during therapy with tigecycline after only brief exposure to the drug. Patients receiving tigecycline for Acinetobacter should be monitored for the development of clinical resistance, and isolates should be monitored for evidence of microbiologic resistance.

Update in the treatment of non-influenza respiratory virus infection in solid organ transplant recipients.

INTRODUCTION: Despite the improved outcomes in solid organ transplantation with regard to prevention of rejection and increased patient and graft survival, infection remains a common cause of morbidity and mortality. Respiratory viruses are a frequent and potentially serious cause of infection after solid organ transplantation. Furthermore, clinical manifestations of respiratory virus infection (RVI) may be more severe and unusual in solid organ transplant recipients (SOTRs) compared with the non-immunocompromised population. Areas covered: This article reviews the non-influenza RVIs that are commonly encountered in SOTRs. Epidemiologic and clinical characteristics are highlighted and available treatment options are discussed. Expert opinion: New diagnostic tools, particularly rapid molecular assays, have expanded the ability to identify specific RVI pathogens in SOTRs. This is not only useful from a treatment standpoint but also to guide infection control practices. More data are needed on RVIs in the solid organ transplant population, particularly regarding their effect on rejection and graft dysfunction. There is also a need for new antiviral agents active against these infections as well as markers that can identify which patients would most benefit from treatment.

Increased risk of PTLD in lung transplant recipients with cystic fibrosis.

BACKGROUND: Post-transplant lymphoproliferative disease (PTLD) is an important cause of morbidity and mortality following lung transplantation. Recipients with cystic fibrosis (CF) may have an increased risk of PTLD although the literature is limited to single center cohorts. Our primary aim is to examine PTLD in an adult lung transplant population by utilizing the International Society for Heart and Lung Transplantation Registry. METHODS: We studied 30,598 adult recipients of lung transplants performed between 1999 and 2011. The primary outcome was development of and time to PTLD. In addition to indication for transplant, other predictors examined included Epstein-Barr virus (EBV) and cytomegalovirus (CMV) serostatus, gender, and age. Outcomes were assessed with univariable and multivariable Cox proportional hazard models to obtain hazard ratios (HR). RESULTS: 17% of the cohort had a diagnosis of CF. PTLD developed in 2% of CF recipients compared to 1% for non-CF recipients (p<0.001). Compared to non-CF recipients, CF recipients had higher prevalence of EBV and CMV seronegativity and higher prevalences of high risk EBV and CMV mismatch (D+/R-). There is a significant association between CF and the development of PTLD [HR 1.66 (95% CI 1.30-2.12)]. Stratified multivariable analysis controlling for age revealed EBV negative non-CF recipients have an almost 2 fold increased risk of developing PTLD, whereas EBV negative CF recipients had an almost 6.5 fold increased risk. CONCLUSIONS: CF recipients have a higher risk for PTLD compared to non-CF recipients. Further studies are needed to account for additional risk factors and management in this population post-transplant.

Trimethoprim-sulfamethoxazole as a viable treatment option for infections caused by methicillin-resistant Staphylococcus aureus.

OBJECTIVE: To review available data regarding the efficacy of trimethoprim-sulfamethoxazole (TMP-SMX) for the treatment of infections caused by methicillin-resistant Staphylococcus aureus (MRSA). DATA SOURCES: A MEDLINE search was performed (January 1966-December 2003) using the search terms Staphylococcus aureus , sulfamethoxazole, trimethoprim, co-trimoxazole, and methicillin resistance. Abstracts from infectious diseases meetings also were reviewed. DATA SYNTHESIS: The reported rate of TMP-SMX resistance in S. aureus is highly variable. From a mechanistic standpoint, TMP-SMX resistance among MRSA appears to be distinct from multidrug resistance, although some anecdotal reports suggest otherwise. Clonal outbreaks of MRSA resistant to TMP-SMX have been described; of these, the Brazilian clone has more often been resistant to TMP-SMX than the Iberian clone. Rates of TMP-SMX resistance are particularly high in institutions serving large numbers of patients infected by the human immunodeficiency virus, due to increased exposure for Pneumocystis prophylaxis. Limited studies and case reports have found TMP-SMX useful against infections caused by MRSA. CONCLUSIONS: A large body of anecdotal data, but only one randomized clinical trial, indicates the effectiveness of TMP-SMX as a treatment for MRSA infections. Double-blind, randomized controlled trials are needed to compare the two available oral agents-TMP-SMX and linezolid-against MRSA.

Late-onset drug fever associated with minocycline: case report and review of the literature.

A 15-year-old Caucasian boy experienced severe fever, fatigue, and a 40-lb weight loss after 2 years of minocycline therapy. A workup for infectious causes was negative. One week after minocycline discontinuation, the patient reported that his fever had resolved. Two months later, he reported full resolution of symptoms, weight gain, and a return to normal activity. An objective causality assessment indicated that his illness probably was caused by minocycline, which is considered a safe drug; however, it has been associated with rare serious adverse effects. This patient's presentation of fever was noteworthy not only because minocycline is a rare cause of drug fever, but also because of the delayed onset. Clinicians should be aware that minocycline may cause severe fever and illness even after an extended period of drug exposure.

Correlation of lamotrigine concentrations between serum and saliva.

STUDY OBJECTIVE: To compare the relationship between serum and salivary concentrations of lamotrigine in pediatric and adult epilepsy populations. DESIGN: Paired-sample pharmacokinetic study. SETTING: University neurology clinic. PATIENTS: Thirty-seven patients with epilepsy, aged 2-60 years, who were taking lamotrigine and whose physicians had ordered a lamotrigine serum concentration. MEASUREMENTS AND MAIN RESULTS: Patients spit a minimum of 0.25 ml into a cup to provide saliva samples. Blood samples were obtained by phlebotomy. Serum and salivary lamotrigine concentrations were determined by high-performance liquid chromatography. Linear regression analysis was used to evaluate correlations. Six patients' results were omitted due to the lack of a serum or saliva specimen or clearly erroneous results, leaving 31 patients for analysis. There was a strong correlation between the serum results reported by two reference laboratories (coefficient of correlation [r] = 0.988). The correlations between salivary and serum lamotrigine concentrations were similar for reference laboratory A (r = 0.81) and reference laboratory B (r = 0.84). Saliva:serum concentration ratios ranged from 0.41-1.26 (mean +/- SD 0.62 +/- 0.19) for reference laboratory A and from 0.40-1.19 ((mean +/- SD 0.64 +/- 0.18) for reference laboratory B. CONCLUSION: There is a good correlation between salivary and serum concentrations for lamotrigine. However, there is wide interpatient variability in the saliva:serum ratio. The data suggest that salivary monitoring may play a role in the monitoring of lamotrigine for adult and pediatric patients.

Topiramate concentration in saliva: an alternative to serum monitoring.

This study examines the relationship between serum and saliva topiramate concentrations, and attempts to determine if saliva may be a useful alternative to serum for therapeutic monitoring. Saliva and blood specimens were collected from 31 epilepsy patients (mean age 10.5 +/- 6.0 years; range 2.5 years to 24.8 years), and topiramate concentrations were determined by fluorescence polarization immunoassay. One patient's results were omitted because the saliva concentration was below the limit of quantitation of the assay. A strong correlation exists between serum and saliva topiramate concentrations (adjusted r(2) = 0.97, n = 30, P < 0.0001). The mean fraction of saliva to serum concentration is 89.8% +/- 12.1% (range 62.9% to 112.7%). The results of this study support the use of saliva as a viable alternative to serum for monitoring topiramate therapy. Topiramate concentration in saliva: an alternative to serum monitoring.

Balance of academic responsibilities of clinical track pharmacy faculty in the United States: a survey of select American College of Clinical Pharmacy Practice and Research Network Members.

STUDY OBJECTIVES: To characterize the balance of clinical and academic responsibilities of clinical track pharmacy faculty in the United States and evaluate organizational structures that promote satisfactory balance between these responsibilities. DESIGN: Prospective cross-sectional survey. SETTING: A 22-item online survey was developed and distributed via Qualtrics software. PARTICIPANTS: Clinical faculty members of the American College of Clinical Pharmacy Adult Medicine, Ambulatory Care, Cardiology, Critical Care, Gastrointestinal/Liver/Nutrition, Immunology/Transplantation, Infectious Disease, and Pediatrics Practice and Research Networks (PRNs) were invited to participate via the PRN electronic mailing list. MEASUREMENTS AND MAIN RESULTS: The survey comprised questions related to demographics, organizational structure, and balance of clinical and academic responsibilities. A total of 344 participants responded to some or all of the survey questions. The demographics were relatively equally balanced between faculty at state and private academic institutions, academic rank, and practice setting. Expected and actual effort allocations were similar for each of the clinical and academic responsibilities, with direct patient care and clinical teaching representing more than 50% effort allocation cumulatively. Clinical faculty at state institutions devoted a larger proportion of time to clinical service, whereas clinical faculty at private institutions devoted a greater proportion of time to didactic teaching. When asked about time constraints, 157 (69.8%) of the 225 survey participants responding to this question did not believe they had sufficient time to fulfill their nonclinical academic needs. Clinical faculty who were provided "protected time" away from clinical service had a significantly more favorable opinion of this question. CONCLUSION: Most of the clinical track pharmacy faculty indicated that they have insufficient time to fulfill their nonclinical academic responsibilities. Provision of protected time may alleviate some of these time constraints.