Clinical Management and Outcomes of Nontuberculous Mycobacterial Infections in Solid Organ Transplant Recipients: A Multinational Case-control Study.

BACKGROUND: The management and outcomes of nontuberculous mycobacterial (NTM) infections in solid organ transplant (SOT) recipients are poorly characterized. We aimed to describe the management and 1-y mortality of these patients. METHODS: Retrospective, multinational, 1:2 matched case-control study included SOT recipients aged 12 y old or older diagnosed with NTM infection between January 1, 2008, and December 31, 2018. Controls were matched on transplanted organs, NTM treatment center, and posttransplant survival at least equal to the time to NTM diagnosis. The primary aim was 1-y mortality after NTM diagnosis. Differences between cases and controls were compared using the log-rank test, and Cox regression models were used to identify factors associated with mortality at 12 mo among cases. RESULTS: In 85 patients and 169 controls, the median age at the time of SOT was 54 y (interquartile range, 40-62 y), 59% were men, and the lungs were the most common site of infection after SOT (57.6%). One-year mortality was significantly higher in cases than in controls (20% versus 3%; P < 0.001), and higher mortality was associated with lung transplantation (hazard ratio 3.27; 95% confidence interval [1.1-9.77]; P = 0.034). Median time (interquartile range) from diagnosis to treatment initiation (20 [4-42] versus 11 [3-21] d) or the reduction of net immunosuppression (36% versus 45%, hazard ratio 1.35 [95% CI, 0.41-4.43], P = 0.618) did not differ between survivors and those who died. CONCLUSIONS: NTM disease in SOT recipients is associated with a higher mortality risk, especially among lung transplant recipients. Time to NTM treatment and reduction in net immunosuppression were not associated with mortality.

Lower Energy Excitation of Water Soluble Near-Infrared Emitting Mixed-Ligand Metallacrowns.

By combining advantages of two series of lanthanide(III)/zinc(II) metallacrowns (MCs) assembled using pyrazine- (pyzHA2- ) and quinoxaline- (quinoHA2- ) hydroximate building blocks ligands, we created here water-soluble mixed-ligand MCs with extended absorption to the visible range. The YbIII analogue demonstrated improved photophysical properties in the near-infrared (NIR) range in cell culture media, facilitating its application for NIR optical imaging in living HeLa cells.

Risk Factors for Nontuberculous Mycobacteria Infections in Solid Organ Transplant Recipients: A Multinational Case-Control Study.

BACKGROUND: Risk factors for nontuberculous mycobacteria (NTM) infections after solid organ transplant (SOT) are not well characterized. Here we aimed to describe these factors. METHODS: Retrospective, multinational, 1:2 matched case-control study that included SOT recipients ≥12 years old diagnosed with NTM infection from 1 January 2008 to 31 December 2018. Controls were matched on transplanted organ, NTM treatment center, and post-transplant survival greater than or equal to the time to NTM diagnosis. Logistic regression on matched pairs was used to assess associations between risk factors and NTM infections. RESULTS: Analyses included 85 cases and 169 controls (59% male, 88% White, median age at time of SOT of 54 years [interquartile range {IQR} 40-62]). NTM infection occurred in kidney (42%), lung (35%), heart and liver (11% each), and pancreas transplant recipients (1%). Median time from transplant to infection was 21.6 months (IQR 5.3-55.2). Most underlying comorbidities were evenly distributed between groups; however, cases were older at the time of NTM diagnosis, more frequently on systemic corticosteroids and had a lower lymphocyte count (all P < .05). In the multivariable model, older age at transplant (adjusted odds ratio [aOR] 1.04; 95 confidence interval [CI], 1.01-1.07), hospital admission within 90 days (aOR, 3.14; 95% CI, 1.41-6.98), receipt of antifungals (aOR, 5.35; 95% CI, 1.7-16.91), and lymphocyte-specific antibodies (aOR, 7.73; 95% CI, 1.07-56.14), were associated with NTM infection. CONCLUSIONS: Risk of NTM infection in SOT recipients was associated with older age at SOT, prior hospital admission, receipt of antifungals or lymphocyte-specific antibodies. NTM infection should be considered in SOT patients with these risk factors.

Long-term risk of hepatocellular carcinoma mortality in 23220 hospitalized patients treated with micafungin or other parenteral antifungals.

BACKGROUND: Liver tumours observed in rats exposed to micafungin led to a black box warning upon approval in Europe in 2008. Micafungin's risk for liver carcinogenicity in humans has not been investigated. We sought to describe the risk of fatal hepatocellular carcinoma (HCC) among persons who received micafungin and other parenteral antifungals (PAFs) with up to 12 years of follow-up. METHODS: We assembled a US multicentre cohort of hospitalized patients who received micafungin or other PAFs between 2005 and 2012. We used propensity score (PS) matching on patient characteristics from electronic medical records to compare rates of HCC mortality identified through the National Death Index though to the end of December 2016. We computed HRs and 95% CIs. RESULTS: A total of 40110 patients who received a PAF were identified; 6903 micafungin recipients (87% of those identified) were successfully matched to 16317 comparator PAF users. Ten incident HCC deaths, one in the micafungin-exposed group and nine among comparator PAF users, occurred in 71285 person-years of follow-up. The HCC mortality rate was 0.05 per 1000 person-years in micafungin patients and 0.17 per 1000 person-years in comparator PAF patients. The PS-matched HR for micafungin versus comparator PAF was 0.29 (95% CI 0.04-2.24). CONCLUSIONS: Both micafungin and comparator PAFs were associated with HCC mortality rates of <0.2 per 1000 person-years. Given the very low event rates, any potential risk for HCC should not play a role in clinical decisions regarding treatment with micafungin or other PAFs investigated in this study.

Adverse Effects Associated with Long-Term Administration of Azole Antifungal Agents.

Azole antifungals are first-line options in the prophylaxis and treatment of invasive fungal infections. They are often used for prolonged (weeks to months) periods of time, particularly in patients with hematologic malignancies, or in those who have received a solid organ or hematopoietic stem cell transplant. Long-term use of azoles is associated with hepatotoxicity and hormone-related effects, including gynecomastia, alopecia, decreased libido, oligospermia, azoospermia, impotence, hypokalemia, hyponatremia, and (rarely) adrenal insufficiency. Voriconazole and posaconazole have been associated with peripheral neuropathies, and itraconazole and voriconazole with pancreatitis. In addition, voriconazole has been associated with periostitis, phototoxic reactions, and squamous cell carcinoma. Since many at-risk patients are commonly receiving multiple medications, it can be difficult for care providers to identify antifungal agent causality or contribution to patient symptoms. Knowledge and recognition of adverse events caused by azoles, leading to dose reduction or discontinuation, can generally reverse these adverse events.

Metals in Medicine: The Therapeutic Use of Metal Ions in the Clinic.

Metal ions are indispensable for living organisms. However, the roles of metal ions in humans is complex, and remains poorly understood. Imbalances in metal ion levels, due to genetic or environmental sources, are associated with a number of significant health issues. However, in clinical medicine, the role of metal ions and metal-based drugs is notable in three major areas: as metal-related diseases; as metal-based medicines (including drugs, imaging agents, and metal chelators); and as agents of metal-based toxicity.

Building a Trojan Horse: Siderophore-Drug Conjugates for the Treatment of Infectious Diseases.

Antimicrobial resistance is a major global health problem, and novel approaches to solving this crisis are urgently required. The 'Trojan Horse' approach to solving this problem capitalizes on the innate need for iron by pathogens. Siderophores are low-molecular-weight iron chelators secreted extracellularly by pathogens to scavenge iron. Once bound to iron, the iron-siderophore complex returns to the pathogen to deliver its iron treasure. "Smuggling" antimicrobials into the pathogen is accomplished by linking them to siderophores for transport. While simple in concept, it has taken many decades of work to accomplish the difficult hurdle of transporting antimicrobials across the cell membranes of pathogens. This review discusses information learned about siderophore structure, production, and transport, and lessons learned from the successes and failures of siderophore-conjugate drugs evaluated during the development of novel agents using the 'Trojan horse' approach.

Are In Vitro Susceptibilities to Azole Antifungals Predictive of Clinical Outcome in the Treatment of Candidemia?

The purpose of this review is to critically analyze published data evaluating the impact of azole pharmacokinetic and pharmacodynamic parameters, MICs, and Candida species on clinical outcomes in patients with candidemia. Clinical breakpoints (CBPs) for fluconazole and voriconazole, which are used to determine susceptibility, have been defined by the Clinical and Laboratory Standards Institute (CLSI) for Candida species. Studies evaluating the relationship between treatment efficacy and in vitro susceptibility, as well as the pharmacodynamic targets, have been conducted in patients treated with fluconazole for candidemia; however, for species other than Candida albicans and Candida glabrata, and for other forms of invasive candidiasis, data remain limited and randomized trials are not available. Limited data evaluating these relationships with voriconazole are available. While pharmacodynamic targets for posaconazole and isavuconazole have been proposed based upon studies conducted in murine models, CBPs have not been established by CLSI. Fluconazole remains an important antifungal agent for the treatment of candidemia, and data supporting its use based on in vitro susceptibility are growing, particularly for C. albicans and C. glabrata Further investigation is needed to establish the roles of voriconazole, posaconazole, and isavuconazole in the treatment of candidemia and for all agents in the treatment of other forms of invasive candidiasis.

Survival in Patients with Candida glabrata Bloodstream Infection Is Associated with Fluconazole Dose.

Robust pharmacodynamic indices that align fluconazole dose or exposure with outcomes in invasive candidiasis due to Candida glabrata remain elusive. The purpose of this retrospective multicenter study was to evaluate a cohort of 127 patients with C. glabrata fungemia treated with fluconazole, using adjusted analyses to identify risk factors for 28-day death. No significant correlations were found between fluconazole area under the curve (AUC), AUC/MIC ratio, or MIC and survival. In multivariate logistic regression analyses, however, higher average fluconazole dose (odds ratio [OR], 1.006 [95% confidence interval [CI], 1.001 to 1.010]; P = 0.008), average fluconazole dose of ≥400 mg (OR, 3.965 [95% CI, 1.509 to 10.418]; P = 0.005), and higher fluconazole dose on day 1 of therapy (OR, 1.007 [95% CI, 1.002 to 1.011]; P = 0.002) were found to be independent predictors of 28-day survival. Additionally, the presence of a central venous catheter at the time of infection was found to be a significant risk factor for death. In conclusion, we found fluconazole dose to be an independent predictor of 28-day survival for patients with C. glabrata fungemia, with doses of ≥400 mg/day being associated with 28-day survival rates approaching 90%. These data indicate the use and efficacy of fluconazole in the treatment of this serious infection. Aggressive dosing appears to be necessary when fluconazole is used for the treatment of C. glabrata fungemia, irrespective of MIC.

The Battle for Iron between Humans and Microbes.

BACKGROUND: Iron is an essential micronutrient for bacteria, fungi, and humans; as such, each has evolved specialized iron uptake systems to acquire iron from the extracellular environment. OBJECTIVE: To describe complex 'tug of war' for iron that has evolved between human hosts and pathogenic microorganisms in the battle for this vital nutrient. METHODS: A review of current literature was performed, to assess current approaches and controversies in iron therapy and chelation in humans. RESULTS: In humans, sequestration (hiding) of iron from invading pathogens is often successful; however, many pathogens have evolved mechanisms to circumvent this approach. CONCLUSION: Clinically, controversy continues whether iron overload or administration of iron results in an increased risk of infection. The administration of iron chelating agents and siderophore- conjugate drugs to infected hosts seems a biologically plausible approach as adjunctive therapy in the treatment of infections caused by pathogens dependent on host iron supply (e.g. tuberculosis, malaria, and many bacterial and fungal pathogens); however, thus far, studies in humans have proved unsuccessful.

Short-term risk of liver and renal injury in hospitalized patients using micafungin: a multicentre cohort study.

BACKGROUND: Although echinocandins are generally well tolerated, there is little information on the frequency with which renal and hepatic adverse effects occur during use of micafungin or other parenteral antifungal (PAF) agents in clinical practice. METHODS: MYCOS is a multicentre cohort study of adult and paediatric patients who received micafungin or other PAFs between 2005 and 2012 at seven tertiary care hospitals from six centres in the USA. PAF cohort controls were selected through propensity score (PS) matching to micafungin recipients using clinical characteristics, other treatments, procedures and hospital service where PAF treatment was initiated. Analysis was restricted to patients without chronic liver and kidney conditions at the time of cohort entry. Treatment-emergent hepatic and renal injury was documented by changes in liver enzymes or estimated glomerular filtration rate through 30 days following completion of PAF treatment. Comparisons were quantified using the HR from a proportional hazards analysis. RESULTS: There were 2970 micafungin recipients PS matched to 6726 recipients of comparator PAFs. Balance was achieved in all baseline covariates between treatment groups. There were similar rates of hepatic injury (micafungin, 13 events per 100 patients and other PAF, 12 per 100; HR = 0.99; 95% CI 0.86-1.14) and lower rates of renal injury (micafungin, 63 events per 100 patients and other PAF, 65 per 100; HR = 0.93; 95% CI 0.87-0.99) for micafungin recipients versus PAF comparators. CONCLUSION: For a wide spectrum of underlying conditions, we observed no increase in liver injury by micafungin and possibly a reduced risk of renal dysfunction in comparison with other PAF medications.

Antifungal Prophylaxis in Lung Transplant Recipients.

Invasive fungal infection remains a serious postoperative complication in lung transplant recipients and is associated with significant morbidity and mortality. Although most lung transplant centers use antifungal prophylaxis, consensus on the strategy, choice of antifungal agent(s), route of administration, and duration of prophylaxis have not been established. This review provides an overview of the epidemiology and risk factors for common fungal infections seen in lung transplant recipients, evaluates the clinical efficacy and toxicity of the various antifungal agents used to prevent infection, and offers recommendations and opportunities for future research. Currently available data evaluating the efficacy of antifungal prophylaxis strategies is limited by a lack of prospective, randomized clinical trial data and variability in patient populations, prophylactic and immunosuppressive strategies, dosing, durations of use of antifungal agents, and definitions of invasive infection. There is controversy regarding significant risk factors for invasive fungal infection, which has limited the development and validation of targeted prophylactic strategies. Inhaled formulations of amphotericin B remain the most widely studied option for universal prophylaxis and have been shown to be effective in reducing the incidence of invasive Aspergillosis as compared with no prophylaxis. Concern over early postoperative extrapulmonary infection may suggest a benefit of initial prophylaxis with a systemic azole. Long-term use of systemic antifungals is not optimal due to emerging evidence of long-term toxicities. Multicenter, randomized trials are needed to ascertain the optimal prophylactic strategy in lung transplant recipients. New agents and delivery mechanisms may offer additional opportunities for comparative research.

Isavuconazole: A New Option for the Management of Invasive Fungal Infections.

OBJECTIVE: To review the pharmacology, chemistry, in vitro susceptibility, pharmacokinetics, clinical efficacy, safety, tolerability, dosage, and administration of isavuconazole, a triazole antifungal agent. DATA SOURCES: Studies and reviews were identified through an English language MEDLINE search (1978 to March 2015) and from http://www.clinicaltrials.gov, Food and Drug Administration (FDA) briefing documents, program abstracts from international symposia, and the manufacturer's Web site. STUDY SELECTION AND DATA EXTRACTION: All published and unpublished trials, abstracts, in vitro and preclinical studies, and FDA briefing documents were reviewed. DATA SYNTHESIS: Isavuconazole has activity against a number of clinically important yeasts and molds, including Candida spp, Aspergillus spp, Cryptococcus neoformans, and Trichosporon spp and variable activity against the Mucorales. Isavuconazole, available for both oral and intravenous administration, is characterized by slow elimination allowing once-daily dosing, extensive tissue distribution, and high (>99%) protein binding. The most commonly reported adverse events, which are mild and limited in nature, include nausea, diarrhea, and elevated liver function tests. Its drug interaction potential appears to be similar to other azole antifungals but less than those observed with voriconazole. Comparative trials are under way or have been recently completed for the treatment of candidemia, invasive candidiasis and aspergillosis, and rare mold infections. CONCLUSIONS: Isavuconazole has a broad spectrum of activity and favorable pharmacokinetic properties, providing an advantage over other currently available broad-spectrum azole antifungals and a clinically useful alternative to voriconazole for the treatment of invasive aspergillosis. It may also prove useful for the treatment of candidemia and invasive mold infections; however, these indications await the results of clinical trials.

Risk factors for systemic vancomycin exposure following administration of oral vancomycin for the treatment of Clostridium difficile infection.

OBJECTIVE: To identify risk factors for systemic exposure to vancomycin (VAN) following administration of oral vancomycin (POV) for the treatment of Clostridium difficile infection (CDI). DESIGN: Prospective, observational, single-center case series. SETTING: Academic medical center. PATIENTS: Hospitalized patients with suspected or confirmed CDI who received POV for at least 5 days. INTERVENTION: Random VAN serum levels were obtained on days 5, 10, and weekly thereafter in patients treated for ≥ 5 days with POV without concomitant intravenous VAN. MEASUREMENTS AND RESULTS: Of 117 random VAN serum levels from 85 patients, 58 patients (68.2%) had one or more detectable (≥ 0.05 µg/ml) levels and 15 (17.6%) of 85 patients had one or more levels > 2.5 µg/ml. Risk factors for detectable VAN exposure following administration of POV included POV dosages > 500 mg/day (odds ratio [OR] 35.83, 95% confidence interval [CI] 7.56-169.8), the presence of severe CDI (OR 4.11, 95% CI 2.76-10.83, p=0.028), intensive care unit (ICU) admission (OR 3.80, 95% CI 1.02-14.21, p=0.032), and the administration of POV ≥ 10 days (OR 6.71, 95% CI 1.81-24.83, p=0.0025). Risk factors for exposure to serum VAN concentrations > 2.5 µg/ml included the presence of gastrointestinal (GI) pathology (OR 5.22, 95% CI 3.45-18.3, p=0.031), ICU admission (OR 3.21, 95% CI 1.40-10.28, p=0.022), the use of VAN retention enemas (OR 4.73, 95% CI 2.42-20.39, p=0.036), and having a creatinine clearance ≤ 50 ml/minute or undergoing hemodialysis or continuous renal replacement therapy (OR 4.03, 95% CI 1.26-12.84, p=0.039). CONCLUSIONS: Serum VAN levels were detected in 58 (68.2%) of 85 patients receiving POV for CDI. Risk factors for systemic exposure to VAN following administration of POV included ICU admission; VAN dosages > 500 mg/day; administration ≥ 10 days or as retention enemas; and the presence of severe CDI, renal dysfunction, or inflammatory conditions of the GI tract. Unique to our study, we identified ICU admission and the concomitant use of VAN retention enemas to be significant risk factors for systemic exposure to VAN.

Real-world experience with echinocandin MICs against Candida species in a multicenter study of hospitals that routinely perform susceptibility testing of bloodstream isolates.

Reference broth microdilution methods of Candida echinocandin susceptibility testing are limited by interlaboratory variability in caspofungin MICs. Recently revised Clinical and Laboratory Standards Institute (CLSI) breakpoint MICs for echinocandin nonsusceptibility may not be valid for commercial tests employed in hospital laboratories. Indeed, there are limited echinocandin susceptibility testing data from hospital laboratories. We conducted a multicenter retrospective study of 9 U.S., Australian, and New Zealand hospitals that routinely tested Candida bloodstream isolates for echinocandin susceptibility from 2005 to 2013. Eight hospitals used Sensititre YeastOne assays. The Candida spp. were C. albicans (n=1,067), C. glabrata (n=911), C. parapsilosis (n=476), C. tropicalis (n=185), C. krusei (n=104), and others (n=154). Resistance and intermediate rates were ≤1.4% and ≤3%, respectively, for each echinocandin against C. albicans, C. parapsilosis, and C. tropicalis. Resistance rates among C. glabrata and C. krusei isolates were ≤7.5% and ≤5.6%, respectively. Caspofungin intermediate rates among C. glabrata and C. krusei isolates were 17.8% and 46.5%, respectively, compared to ≤4.3% and ≤4.4% for other echinocandins. Using CLSI breakpoints, 18% and 19% of C. glabrata isolates were anidulafungin susceptible/caspofungin nonsusceptible and micafungin susceptible/caspofungin nonsusceptible, respectively; similar discrepancies were observed for 38% and 39% of C. krusei isolates. If only YeastOne data were considered, interhospital modal MIC variability was low (within 2 doubling dilutions for each agent). In conclusion, YeastOne assays employed in hospitals may reduce the interlaboratory variability in caspofungin MICs against Candida species that are observed between reference laboratories using CLSI broth microdilution methods. The significance of classifying isolates as caspofungin intermediate and anidulafungin/micafungin susceptible will require clarification in future studies.

The evolving role of antifungal susceptibility testing.

Although increasing numbers of hospital microbiology laboratories are performing antifungal susceptibility testing (AST), its routine use is uncommon. The utility of AST is founded on the belief that susceptibility (or resistance) of an agent allows some prediction of clinical outcome. This review provides an overview of the development of antifungal susceptibility testing methodology, including wild-type minimum inhibitory concentration (MIC) distributions, epidemiologic breakpoints, and Interpretive Clinical Breakpoints for antifungal agents. In addition, we examine the current clinical utility of AST and the clinical data support utilized in the development of clinical breakpoints (CBP) for common pathogens causing invasive fungal infections. In the treatment of fungal infections, identifying consistent correlations between MICs - or susceptibility category - and clinical outcomes is an ongoing challenge, and current data sets are insufficient for many drugs and pathogens to enable the development, revision, or confirmation of CBPs. Antifungal susceptibility testing is of current value, but further research in many areas is needed before MICs are independently used to guide treatment decisions.

Metal ions and infectious diseases. An overview from the clinic.

Trace elements (TEs) are required by both humans and bacterial pathogens. Although metal ion homeostasis is tightly controlled in humans, growing evidence suggests that pathogens utilize a variety of means designed to circumvent the sequestration of TEs. Colonizing pathogenic microorganisms employ a variety of strategies to sense, acquire, store, and export metal ions in the vertebrate host which include the biosynthesis and utilization of siderophores, and the expression of high-affinity metal-ion transporters. For iron, selenium, and zinc, significant correlations have been shown between TE levels in plasma, serum, or tissues, and the prevention or treatment of a variety of infectious diseases; fewer such data exist for copper, chromium, or manganese. TEs are often employed as antioxidants, and as supplements in patients with TE-deficient states. The role of TE supplementation in humans as antioxidants remains controversial, but has demonstrated significant benefit in the role of selenium for patients with sepsis, and of zinc for the prevention of several infectious diseases.

Fluconazole versus an echinocandin for Candida glabrata fungaemia: a retrospective cohort study.

OBJECTIVES: We studied whether fluconazole or echinocandin treatment of Candida glabrata fungaemia results in superior outcomes. METHODS: A multicentre, retrospective study was performed with 224 adult patients who received ≥ 5 days of therapy with either fluconazole or an echinocandin as their first antifungal treatment after collection of a blood culture that grew C. glabrata. The primary outcome was day 14 complete response. RESULTS: Patients in the echinocandin group were generally more ill, both at baseline and at the time of the index culture. Day 14 complete response was obtained in 58/127 (46%) and 50/97 (52%) of the fluconazole and echinocandin patients, respectively (P=0.383). Logistic regression found intensive care unit admission to be associated with failure [OR 0.456 (0.217-0.957), P=0.038] and echinocandin therapy to be associated with day 14 complete response [OR 2.305 (1.124-4.727), P=0.023]. Twenty-eight day survival was similar between the fluconazole and echinocandin groups and logistic regression did not reveal antifungal therapy choice to be independently predictive of mortality. For patients treated with fluconazole, a dose:MIC ratio >12.5 (when compared with a ratio ≤ 12.5) was associated with a significantly higher day 14 complete response [4/20 (20%) ≤ 12.5 versus 50/102 (49%) >12.5, P=0.025]. CONCLUSIONS: Severity of illness and choice of antifungal predict response in patients with C. glabrata fungaemia. Antifungal choice, however, does not influence mortality. In addition, new CLSI C. glabrata fluconazole susceptibility breakpoints are predictive of response when fluconazole is dosed appropriately.

Ceftaroline fosamil: a novel broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus.

OBJECTIVE: To review the pharmacology, microbiology, chemistry, in vitro activity, pharmacokinetics, clinical efficacy, safety, dosage, and administration of ceftaroline fosamil (Teflaro, Forest Laboratories, Inc.), a novel parenteral broad-spectrum cephalosporin approved by the Food and Drug Administration (FDA) on October 29, 2010, for the treatment of adults with acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). DATA SOURCES: A search of MEDLINE (1966-July 2011) using the search terms ceftaroline fosamil, ceftaroline, TAK-599, PPI-0903, PPI-0903M, and T-91825 was performed. Supplementary sources included program abstracts from the Interscience Conference on Antimicrobial Agents and Chemotherapy, American Society of Microbiology, European Congress on Clinical Microbiology and Infectious Diseases, and the Infectious Diseases Society of America from 2005 to 2010, as well as information available from the manufacturer's Web site. STUDY SELECTION AND DATA EXTRACTION: All English-language articles identified from the data sources were evaluated. In vitro, preclinical, and Phase 1, 2, and 3 clinical trials were included. DATA SYNTHESIS: Clinical trials have been conducted evaluating use of ceftaroline for treatment of ABSSSI and CABP. Safety data from Phase 1, 2, and 3 clinical trials suggest that it is well tolerated and has a safety and tolerability profile common to the cephalosporin class. Ceftaroline has excellent in vitro activity against gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), which makes it an attractive monotherapy for the treatment of ABSSSI. However, it lacks activity against problem gram-negative bacteria (eg, Pseudomonas spp.), which will likely limit its use for serious health care-associated infections. While its role in treating CABP is supported by excellent in vitro activity against Streptococcus pneumoniae and clinical efficacy data, currently available comparators may offer some advantages over ceftaroline. Finally, data are lacking to assess its role in the treatment of serious infections due to MRSA (eg, pneumonia, bacteremia). CONCLUSIONS: These considerations should be part of the formulary review process; however, when considering the significant role MRSA plays in ABSSSI in both the community and hospital settings, we believe that ceftaroline will provide clinicians with a welcome option in addition to currently available anti-MRSA therapies for the treatment of ABSSSI.

Dosing and monitoring of trace elements in long-term home parenteral nutrition patients.

BACKGROUND: Trace elements (TEs) dosing and monitoring in home parenteral nutrition (PN) patients vary with their underlying conditions. METHODS: This retrospective observational study evaluated parenteral TE dosing, serum TE concentrations and monitoring, and dose-concentration relationships between TE doses and serum TE concentrations in 26 adult and adolescent home PN patients. RESULTS: There was a total of 40,493 PN days. Average parenteral zinc doses of 9.1 mg/d and 7.6 mg/d resulted in the majority of serum zinc concentrations (90%) within normal range in patients with and without short bowel syndrome (SBS), respectively. Selenium at about 70 mcg/d resulted in about 60% of serum selenium concentrations within normal range, with 38% of values below normal in patients with and without SBS alike. Copper at 1 mg/d resulted in 22.5% of serum copper concentrations above the normal range. The majority of serum manganese (94.6%) and chromium (96%) concentrations were elevated. Serum TE concentrations were infrequently monitored. Significant relationships existed between doses and serum concentrations for zinc (P < .0001), manganese (P = .012), and chromium (P < .0001) but not for selenium or copper. CONCLUSIONS: TE doses in home PN should be individualized and adjusted based on regular monitoring of TE status. In long-term home PN patients, higher zinc and selenium doses may be necessary to maintain their normal serum concentrations. Lower copper doses and restrictions of manganese and chromium supplementation may be needed to avoid their accumulation. Relationships between TE doses and serum TE concentrations vary for each TE and underlying clinical conditions.