Kenneth P. Klinker

Large Retrospective Evaluation of the Effectiveness and Safety of Ceftaroline Fosamil Therapy

ABSTRACT Ceftaroline has been approved for acute bacterial skin infections and community-acquired bacterial pneumonia. Limited clinical experience exists for use outside these indications. The objective of this study was to describe the outcomes of patients treated with ceftaroline for various infections. Retrospective analyses of patients receiving ceftaroline ≥72 h from 2011 to 2013 were included. Clinical and microbiological outcomes were analyzed. Clinical success was defined as resolution of all signs and symptoms of infection with no further need for escalation while on ceftaroline treatment during hospitalization. A total of 527 patients received ceftaroline, and 67% were treated for off-label indications. Twenty-eight percent (148/527) of patients had bacteremia. Most patients (80%) were initiated on ceftaroline after receipt of another antimicrobial, with 48% citing disease progression as a reason for switching. The median duration of ceftaroline treatment was 6 days, with an interquartile range of 4 to 9 days. A total of 327 (62%) patients were culture positive, and the most prevalent pathogen was Staphylococcus aureus, with a frequency of 83% (271/327). Of these patients, 88.9% (241/271) were infected with methicillin-resistant S. aureus (MRSA). Clinically, 88% (426/484) achieved clinical success and hospital mortality was seen in 8% (40/527). While on ceftaroline, adverse events were experienced in 8% (41/527) of the patients and 9% (28/307) were readmitted within 30 days after discharge for the same infection. Patients treated with ceftaroline for both FDA-approved and off-label infections had favorable outcomes. Further research is necessary to further describe the role of ceftaroline in a variety of infections and its impact on patient outcomes.

Real-World Experience with Echinocandin MICs against Candida Species in a Multicenter Study of Hospitals That Routinely Perform Susceptibility Testing of Bloodstream Isolates

ABSTRACT 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.

Multicenter Study of Epidemiological Cutoff Values and Detection of Resistance in Candida spp. to Anidulafungin, Caspofungin, and Micafungin Using the Sensititre YeastOne Colorimetric Method

ABSTRACT Neither breakpoints (BPs) nor epidemiological cutoff values (ECVs) have been established for Candida spp. with anidulafungin, caspofungin, and micafungin when using the Sensititre YeastOne (SYO) broth dilution colorimetric method. In addition, reference caspofungin MICs have so far proven to be unreliable. Candida species wild-type (WT) MIC distributions (for microorganisms in a species/drug combination with no detectable phenotypic resistance) were established for 6,007 Candida albicans, 186 C. dubliniensis, 3,188 C. glabrata complex, 119 C. guilliermondii, 493 C. krusei, 205 C. lusitaniae, 3,136 C. parapsilosis complex, and 1,016 C. tropicalis isolates. SYO MIC data gathered from 38 laboratories in Australia, Canada, Europe, Mexico, New Zealand, South Africa, and the United States were pooled to statistically define SYO ECVs. ECVs for anidulafungin, caspofungin, and micafungin encompassing ≥97.5% of the statistically modeled population were, respectively, 0.12, 0.25, and 0.06 μg/ml for C. albicans, 0.12, 0.25, and 0.03 μg/ml for C. glabrata complex, 4, 2, and 4 μg/ml for C. parapsilosis complex, 0.5, 0.25, and 0.06 μg/ml for C. tropicalis, 0.25, 1, and 0.25 μg/ml for C. krusei, 0.25, 1, and 0.12 μg/ml for C. lusitaniae, 4, 2, and 2 μg/ml for C. guilliermondii, and 0.25, 0.25, and 0.12 μg/ml for C. dubliniensis. Species-specific SYO ECVs for anidulafungin, caspofungin, and micafungin correctly classified 72 (88.9%), 74 (91.4%), 76 (93.8%), respectively, of 81 Candida isolates with identified fks mutations. SYO ECVs may aid in detecting non-WT isolates with reduced susceptibility to anidulafungin, micafungin, and especially caspofungin, since testing the susceptibilities of Candida spp. to caspofungin by reference methodologies is not recommended.

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.

Clinical and economic impact of antimicrobial stewardship interventions with the FilmArray blood culture identification panel.

The purpose of this study was to evaluate the impact of the FilmArray Blood Culture Identification (BCID) Panel on the management of patients with blood cultures growing gram positive cocci and Candida. We retrospectively compared clinical and economic outcomes between patients during the BCID testing period and a matched historical control group before BCID testing was introduced. A total of 84 BCID patients were matched to 252 historical controls. BCID identification of coagulase negative staphylococci contaminants resulted in shorter post-culture length of stay (P < 0.008) and saved roughly

An In-Depth Analysis of Medication Errors in Hospitalized Patients with HIV

30,000 per 100 patients tested. The BCID led to shorter duration of empirical vancomycin for patients with contaminated blood cultures (P = 0.005) and methicillin-susceptible Staphylococcus aureus bacteremia (P < 0.001). Patients with vancomycin-resistant enterococcal bacteremia received active therapy earlier than historical controls (P = 0.047). The BCID, coupled with antimicrobial stewardship intervention, was a cost effective tool to improve patient care.

Beyond Vancomycin: The Tail of the Lipoglycopeptides

Background It is well recognized that medication errors occur and can affect success in treating patients with HIV/AIDS. However, little information is available describing the prevalence, nature, and causes of medication errors. Objective: To determine the incidence of combination antiretroviral therapy (ART)– and opportunistic infection (OI)–related medication errors and describe the nature and cause(s) of errors to guide future interventions. Methods: A daily antiretroviral utilization report was used to identify adults who were receiving ART and had been admitted to a tertiary care teaching hospital during 2 consecutive months in 2005. Patients’ charts, medication profiles, and medication administration records were reviewed for medication errors such as improper dosing, interactions, drug omissions, and missing doses. Once identified, etiology and cause were further investigated through provider interviews. An interdisciplinary team reviewed each case to establish validity of the error, severity, and cause. Results: Sixty-nine combined ART- and OI-related medication errors were identified in 20 of 26 (77%) evaluated patients, with 2.7 medication errors per patient. Fifty-four percent of the errors occurred within the first 24 hours after admission. Inadequate medication reconciliation on admission caused 21 of 37 (57%) admission-related errors. The most prevalent error types included missing doses (20%), underdosing (13%), overdosing (13%), therapy omission (13%). and drug-drug interaction (12%). The primary cause of errors was provider lack of knowledge. Conclusions: Prospective investigation of medication errors provided in-depth insight into the diverse nature of HIV-related medication errors, risk factors, and potential preventive strategies. System changes such as hard stops in the clinical decision support software and improved medication reconciliation training, and changes in cart-fill time could prevent specific types of errors. Further studies are warranted to evaluate the impact of various strategies for preventing medication errors in the HIV population.

Time to Positivity of Blood Cultures Supports Antibiotic De-escalation at 48 Hours

PURPOSE The purpose of this comparative review is to provide clinical information on the semisynthetic lipoglycopeptides (telavancin, oritavancin, and dalbavancin) for the management of gram-positive infections. METHODS A PubMed search was conducted using the following terms: telavancin, dalbavancin, and oritavancin. Clinical trials evaluating pharmacokinetic properties, pharmacodynamic properties, clinical efficacy, and safety profiles were included in the review. FINDINGS The lipoglycopeptides are approximately 4- to 8-fold more potent than vancomycin against gram-positive organisms, including activity against vancomycin-intermediate or vancomycin-resistant strains of Staphylococcus and Enterococcus species. In addition, oritavancin maintains activity against Enterococcus species harboring vanA operon. Clinical trial data revealed equal efficacy to vancomycin in the management of acute bacterial skin and skin structure infections and, in the case of telavancin, hospital-acquired pneumonia. A benefit of oritavancin and dalbavancin is that a full course of therapy consists of a single- or 2-dose regimen, respectively. These agents are well tolerated with similar adverse event rates to vancomycin. Telavancin requires a thorough assessment before initiation of therapy to minimize the risk of acute kidney injury and teratogenicity. IMPLICATIONS The lipoglycopeptides enhance the antibiotic gram-positive armamentarium at a time when methicillin-resistant Staphylococcus aureus prevalence and overall resistance is at an all-time high. These agents serve to fill different clinical roles in the management of gram-positive infections. On the basis of the available data, telavancin should be considered a plausible agent for the management of gram-positive organisms when patients do not respond or develop adverse effects to vancomycin. Dalbavancin and oritavancin are new therapeutic options, and their potency and pharmacokinetic properties may provide benefit over existing therapies. Clinical trial data indicate that patients with signs or symptoms of skin and skin structure infections may be successfully treated using 1 or 2 doses of these agents. Eliminating the need for inpatient admission, central catheter placement, and/or daily outpatient parenteral antibiotic therapy is a major advance in treatment of skin and skin structure infections. This strategy may reduce costs associated with resource utilization and iatrogenic morbidity, resulting in overall improvements in care.

Acute kidney injury risk associated with piperacillin/tazobactam compared with cefepime during vancomycin therapy in hospitalised patients: a cohort study stratified by baseline kidney function

Background: Appropriate de-escalation of empirical antimicrobial therapy is a fundamental component of antimicrobial stewardship. Concern for the late detection of bloodstream pathogens may undermine early streamlining efforts and subject patients to protracted courses of nonessential therapy. Objective: To quantify the prevalence of bacterial bloodstream infection (BSI) detection after more than 48 hours of culture incubation. We also assessed the impact of antimicrobial therapy delivered prior to blood sample collection. Methods: We retrospectively evaluated time to blood culture positivity (TTP) in adult patients at an academic tertiary care hospital. Microbiology reports were reviewed to identify the TTP for the first positive blood culture bottle for each episode of BSI occurring from February 1, 2011, to July 31, 2011. Isolates were classified as true pathogens or contaminants. Blood culture results after 48 hours of incubation were compared with results after 120 hours of incubation. Results: The median TTP of 416 monomicrobial BSIs and 210 contamination episodes was 13.7 and 24.4 hours, respectively (P < .001). The median TTPs in those who received and did not receive prior antibiotics were 17.0 and 12.8 hours, respectively (P < .001). By 48 hours, 98% of aerobic Gram-positive and Gram-negative BSIs were detected. Culture results at 48 hours were 97% sensitive and had a negative predictive value of 99.8%. Conclusion: Few true BSIs are detected after more than 48 hours of culture incubation. Clinicians may adjust empirical antibiotic coverage at this time with little risk for subsequent bacterial pathogen detection.

Antimicrobial Stewardship in the Emergency Department

Recent studies have found an association between piperacillin/tazobactam when added to vancomycin and acute kidney injury (AKI) risk. However, studies were limited by the small sample size and residual confounding. The aim of this study was to compare the risk of AKI with vancomycin plus piperacillin/tazobactam (VPT) versus vancomycin plus cefepime (VC) and to examine whether pre-existing renal impairment mediates the risk. This was a retrospective cohort study using electronic health records for patients admitted to two hospitals in 2012-2013. The outcome, AKI, was defined as an increase in serum creatinine level of ≥0.3 mg/dL or ≥50% from baseline. Patients were stratified by level of renal impairment as estimated by baseline creatinine clearance. Inverse probability of treatment weighting was used to balance baseline covariates between groups. Cox proportional hazards regression was used to evaluate VPT risk of AKI compared with VC. A total of 935 (17.53%) AKI cases were identified among 5335 patients receiving VPT or VC. VPT was associated with a higher risk of AKI relative to VC, with an adjusted hazard ratio (aHR) of 1.25 [95% confidence interval (CI) 1.11-1.42] in the total population and 1.70 (95% CI 1.44-2.02) in patients with normal baseline renal function. However, no elevated risk was found in patients with prior renal impairment (aHR = 0.81, 95% CI 0.65-1.01). VPT was associated with a higher risk of AKI relative to VC. The association was true in patients with normal renal function but not in those with pre-existing renal impairment.