Infectious Diseases Society of America 47th Annual Meeting
October 29-November 1, 2009; Philadelphia, PA

POSTER

Clinical Experience with Daptomycin for the Treatment of Patients with Bacteremic Skin and Skin-Structure Infections

Philadelphia, PA—Data from the Cubicin® Outcomes Registry and Experience (CORE) 2005-2008, a retrospective, multicenter, observational chart review to assess characteristics and clinical outcome of patients receiving daptomycin, support the use of daptomycin for skin and skin structure infections (SSSI) bacteremia (BSI). Researchers concluded that further study is warranted to characterize high-risk patients for BSI associated with SSSI and to evaluate treatment outcomes.

Findings of the study were presented at the annual IDSA meeting. All patients with SSSI BSI in CORE 2005-2008 were studied, and primary outcome (success, failure, nonevaluable) was investigator-assessed at the end of daptomycin therapy; a secondary outcome was sponsor-assessed where daptomycin discontinued due to adverse event (AE), death (any cause), and/or evidence for lack of clinical response were evaluated as failures. Demographics and efficacy were based on investigator-evaluable population; all patients were included for safety. A standardized case report form and protocol were used to collect demographic, microbiologic, and clinical information on patients who had been treated with daptomycin from 62 separate institutions in the United States from January 2005 through December 2008. After institutional review board approval, clinical information was collected from medical records by trained study investigators. The methods have been previously published (Rolston et al, Am J Med 2007).

Adult patients (≥ 18 yr) with an investigator-defined diagnosis of both bacteremia and an uncomplicated or complicated skin and soft tissue infection were evaluated for inclusion. Specific diagnoses included were complicated SSSI and uncomplicated SSSI. Catheter-related bacteremia was excluded for evaluation. Patients were considered evaluable for efficacy if the response to daptomycin as assessed by the investigator was classified as one of the following: cure; improved; or failure. Nonevaluable patients were excluded from the primary efficacy analysis; however, they were included in the safety analysis. No pre-specified duration of therapy was required for efficacy evaluation.

Results were as follows: 111/2269 (5%) patients with SSSI had concomitant BSI. Eighty-eight out of 111 (79%) patients were evaluable for the primary outcome; 28 of 88 (32%) were > 65 years; 36 of 88 (41%) were diabetic, and 8 of 88 (9%) had peripheral vascular disease. Fifty-six of 88 (64%) had complicated SSSI and 32 of 88 (36%) uncomplicated SSSI; 17 of 88 (19%) had creatinine clearance (CrCl) < 30 ml/min. Seventy-five percent of patients had Staphylococcus sp, 48% of which was methicillin-resistant Staphylococcus aureus (MRSA), 30% had Enterococcus sp (62% of which was vancomycin-resistant enterococci [VRE]). Daptomycin median (min, max) initial dose was 5.5 mg/kg (3.7, 10.0; 42% ≥ 6 mg/kg); length of therapy was 10.5 days (interquartile range 6-21). Eighty-one percent of patients received prior antibiotics: 56% vancomycin; 14% linezolid. The primary outcome of success was 89% (78/88) overall and was 94% (30/32) in patients with MRSA, 63% (10/16) in patients with VRE. Success in patients with a single pathogen was 91% (42/46) and 86% (36/42) in polymicrobial infections. Success was 94% versus 87% when used as first-line therapy versus secondary therapy. No differences in outcomes were observed when assessed by CrCl < 30; abscess or neutropenia. Sponsor-assessed outcome in 93 patients revealed an 80% success rate. Eight out of 111 patients (7%) had 10 AEs possibly related to daptomycin; three were serious. Discontinuation due to AE (n = 5/111) was 4.5%.

Investigators concluded that in this population, daptomycin appears to be a useful agent for treatment of bacteremia associated with skin and soft tissue infections; however, comparative studies are needed to ascertain if there are relative differences as compared with other agents for use in serious skin infections accompanied by bacteremia. Daptomycin appeared to be well tolerated. Adverse events possibly related to daptomycin were mild to severe, and were reported in eight patients, five of whom discontinued therapy.

This study was funded by Cubist Pharmaceuticals.

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POSTER

Outcomes and Characteristics of Patients Treated with Daptomycin for Gram-Positive Catheter-Related Bacteremia

Philadelphia, PA—In patients with catheter-related bacteremia (CRB), catheter removal is generally considered standard-of-care; however, this is not always feasible. This study, presented at the annual IDSA meeting, describes the use of daptomycin in patients with documented Gram-positive (GP) CRB, with and without catheter removal. Researchers concluded that success rates were significantly higher with catheter removal, but daptomycin may be an effective treatment option in patients where removal is not possible. In addition, daptomycin appears to be effective in treating CRB caused by Staphylococus aureus, coagulase-negative staphylococci (CoNS), and enterococci. Further studies may be warranted.

All patients with a diagnosis of CRB and a positive blood culture for a GP pathogen were identified in Cubicin® Outcomes Registry and Experience (CORE®) 2007-2008, a retrospective, multicenter, observational registry. The primary outcome (cure, improved, failure, nonevaluable [NE]) was the investigator assessment at the end of daptomycin therapy; a secondary outcome was the sponsor assessment. The sponsor assessed daptomycin discontinuations due to an adverse event (AE), death from any cause, and any indicator of lack of response as failures. Success was defined as cure or improved. All patients were included in the safety analysis. The methods have been previously published (Rolston et al, Am J Med, 2007).

Two hundred forty patients with CRB were identified, of whom 220 had a documented GP pathogen; 182 were evaluable for outcome. Fifty-two percent of patients (95/182) had their catheters removed. Among the 182 patients, the most common blood pathogens were CoNS (33% [60/182]), Enterococcus spp. (43% [78/182]); vancomycin-resistant Enterococcus (VRE; 65% [51/78]), and S. aureus (27% [50/182]); methcillin-resistant S. aureus (MRSA; 82% [41/50]). There was no association between the type of blood pathogen reported and the rate of catheter removal. There was no difference in the median final daptomycin dose used in patients with and without catheter removal; however, the median [min, max] total duration of daptomycin therapy was longer in the group who had their catheter removed versus those who did not (14 days [2, 61] vs 11 days [1, 49]; P = 0.04). Overall, the median (min, max) final daptomycin dose was 6 mg/kg (3, 14.5). Median (min, max) final daptomycin dose in catheter removal and catheter non-removal groups was 6 mg/kg (3, 14.5) and 6 mg/kg (4, 10), respectively (P = 0.09). In the catheter removal group and catheter not-removed group, 68/95 (72%) and 73/87 (84%) of patients received a daptomycin dose ≥ 6 mg/kg, respectively (P = 0.05). Forty-nine patients (27%) had a creatinine clearance (CrCl) < 30 mL/min at daptomycin initiation. Thirty-seven (76%) received daptomycin every 48 hours, eight (16%) received daptomycin 3 times/week, and four (8%) received daptomycin every 24 hours. Ten percent of patients (n = 22) experienced 37 AEs possibly related to daptomycin; two AEs each in two patients were serious.

This study was funded by Cubist Pharmaceuticals.

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POSTER

Reported Adverse Experiences in Patients with Unknown Immunosuppressive Conditions Vaccinated with VARIVAX™

Philadelphia, PA—The objective of this study, presented at the IDSA annual meeting, was to describe the 14-year safety data regarding reported adverse events (AEs) in patients who were not known to have an immunosuppressive condition (ISC) at the time of vaccination with VARIVAX™ (varicella virus vaccine live), but who were subsequently diagnosed with an ISC post-vaccination and experienced AEs ≤ 42 days post-vaccination. Researchers found that varicella-like rash and pneumonia were the most common AEs reported in patients with an unknown ISC who presented with AEs ≤ 42 days post-vaccination. Pneumonia was only seen in patients with immunodeficiency disorders (IDs). It was concluded that diagnostic evaluations to identify a primary or acquired ID should be considered in patients presenting with a varicella-like rash with pneumonia ≤ 42 days post-vaccination.

VARIVAX™, a live attenuated varicella virus vaccine indicated for vaccination against varicella, is contraindicated in patients with immunosuppressive conditions including blood dyscrasias, leukemia, lymphomas, malignant neoplasm affecting the bone marrow or lymphatic systems, and primary or acquired immunodeficiency states. The Merck & Co., Inc. Worldwide Adverse Experience System database was searched from market introduction (March 17, 1995) to March 16, 2009 for reported AEs in patients with an unknown ISC at the time of vaccination with VARIVAX™, who were subsequently diagnosed with an ISC after vaccination and experienced an AE ≤ 42 days (two times the upper limit of the normal incubation period for varicella zoster virus [VZV]) post-vaccination. Reports were reviewed to identify the types of ISCs and reported AEs.

Thirteen patients were identified (8 with primary or acquired IDs and 5 with oncologic disorders [ONCO]) who had reported AEs ≤ 42 days post-vaccination. Of those with ID, six were classified as primary and two as acquired. Of those with ONCO, four had leukemia (LEU) and one had lymphoma. Among the reported AEs were varicella-like rash (10; 77%), pneumonia (6; 46%), hepatitis (2; 15%), and herpes zoster (HZ; 1; 8%). All six patients with pneumonia had an ID, with one of six pneumonias reported prior to rash onset, three of six reported at the time of rash, and two of six reported after rash onset. The one patient with HZ had LEU. Median time to onset (TTO) from vaccination to onset of varicella-like rash was 19 days post-vaccination for ID and 31 days post-vaccination for ONCO. Twelve specimens for PCR analysis were available from eight of the 13 patients. Vaccine strain VZV (vVZV) was identified in 11 samples (5 from skin, 5 from lung, 1 from liver) and wild-type strain VZV (wtVZV) in one specimen (lung). Nine of 13 reports included recovery status. At the time of the report, eight of the nine patients, including five with pneumonia, were reported as recovered from their AE, while the one patient with lymphoma was reported as not recovered. Five of eight patients with ID had a history of failure to thrive and/or recurrent infections prior to vaccination.

The investigators concluded that the majority of patients with an immunosuppressive condition that was not known at the time of vaccination with VARIVAX™ had an ID. Primary IDs were most common. In some patients, the signs and symptoms associated with an immunodeficiency, such as recurrent infections, oral candidiasis, and failure to thrive, were reported prior to vaccination. Varicella-like rash was the most common and pneumonia the second most common AE reported in patients with an unknown immunosuppressive condition who presented with AEs ≤ 42 days post-vaccination. Pneumonia was reported only in patients with IDs. All patients with pneumonia also had a varicella-like rash. In this population of immunocompromised patients with AEs ≤ 42 days post vaccination, when VZV was detected, it was more likely to be vVZV than wtVZV. Diagnostic evaluations to identify a primary or acquired ID should be considered in patients presenting with varicella-like rash with pneumonia ≤ 42 days post-vaccination. Despite the small number of patients reported and the limitations of postmarketing surveillance, healthcare providers should recognize post-vaccination AEs that may possibly be associated with an immunosuppressive condition that was unknown prior to vaccination. Merck & Co., Inc., will continue to monitor the safety of VARIVAX™.

The funding source for this project was Merck & Co., Inc.

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POSTER

Regional Prevalence of MRSA and Analysis of Ceftobiprole Activity against MRSA from 2006-2008─Results from TRUST and TSN Surveillance

Philadelphia, PA—According to the results of a study presented at the recent IDSA meeting, the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) is high throughout the United States, with rates more than 60% in some regions, and also is high among inpatient (IN) relative to outpatient (OP) populations. In addition, ceftobiprole (BPR) activity against MRSA during the 3 years analyzed showed no major shift in MIC and remained consistent across all regions/patient locations (PLs) evaluated. Investigators concluded that, given the prevalence of MRSA in most regions of the United States, the advent of a novel cephalosporin, such as BPR, with high potency against MRSA and low potential for resistance development, is of great interest. Further monitoring of its clinical utility is needed and as use worldwide increases further, surveillance to monitor for any emerging resistance is warranted.

S. aureus is a prevalent pathogen in both the community and nosocomial environments, and is frequently isolated from patients with skin/wound infections, pneumonia, and bacteremia. MRSA has become more commonly encountered over the past decade, in particular in the community due to the spread of epidemic community-acquired MRSA (CA-MRSA) clones such as USA300. Ceftobiprole is the first cephalosporin with potent activity against MRSA approved for the treatment of complicated skin and skin structure infections (cSSSI) (2007-2008 in Canada, Switzerland, Ukraine; 2009 in Russia and Azerbaijan). The drug is currently under regulatory review for the treatment of cSSSI in the United States and in Europe and is also under development for the treatment of hospital-acquired pneumonia. As resistance can vary by region and patient population, it is important to understand the impact these factors may have on the activity profile of current agents against target pathogens. The purpose of this study was to evaluate the prevalence of MRSA in the United States by region and the activity profile of ceftobiprole against MRSA from IN, OP, and Intensive Care Unit (ICU) clinical isolates from 2006-2008.

S. aureus isolates were collected in the TRUST 10 (2006), 11 (2007), and 12 (2008) surveillance studies (N = 4840), and susceptibility testing against ceftobiprole and comparators was performed centrally by broth microdilution (CLSI M7-A8). MICs were interpreted in accordance with CLSI M100-S18 where appropriate. Current prevalence of MRSA was based on S. aureus clinical U.S. testing data (2006-2008; N = 634,577) from The Surveillance Network (TSN). Trending analysis was based on S. aureus TSN data collected over a 10-year period (1998-2008; N = 1,955,867).

An overall increase in the prevalence of MRSA over the past decade was apparent, with a national prevalence of 53.8% from 2006-2008. MRSA rates varied by patient population, with a large increase in the prevalence of MRSA in the OP population from pre-2003 (< 35%) to post-2005 (> 50%). From 2006-2008, MRSA rates were highest among IN isolates (58.2%); rates among ICU isolates were 54.2% and among OP isolates were 51.4%. MRSA prevalence varied by region based on current TSN data (2006-2008). Regional MRSA rates exceeded 50% in six of nine regions, and 60% in two of nine regions (East and West South Central regions). In MRSA isolates (n = 3,352), overall BPR MIC50/90 was 1/1 μg/mL regardless of region, and all but three isolates (MIC = 4 μg/mL) had BPR MICs ≤2 μg/mL. During this time, the MIC50/90 did not change in most regions except for the West North Central, New England, and East North Central, where MIC90 increased to 2 μg/mL. BPR MIC50/90 in the IN and OP units were 1/1 μg/mL and 1/2 μg/mL in the ICU.

Ceftobiprole had an MIC50/MIC90 of 0.25/0.5 μg/mL against MSSA and 1/1 μg/mL against MRSA. Evaluated MRSA were 100% susceptible to other gram-positive agents (linezolid, daptomycin, vancomycin) with a high degree of resistance to erythromycin (93%), clindamycin (31%), and levofloxacin (65%). Among the evaluated MRSA, the activity profile of ceftobiprole based on MIC50 and MIC90 was largely consistent year to year (1/1 μg/mL) across the evaluated regions and patient populations, with the exception of some subpopulations where an MIC90 of 2 μg/mL was observed (eg, the ICU subpopulation, and 3/9 regions in TRUST 12). Cumulative MICs show nearly identical ceftobiprole activity profiles across patient location and region. Ceftobiprole MICs, though generally twofold higher against MRSA than MSSA, remained < 2 μg/mL for all but three evaluated MRSA isolates (0.1%) which had MICs of 4 μg/mL.

Investigators concluded that MRSA prevalence has increased over the past decade, though rates vary by region and patient population; MRSA rates are > 60% in some regions relative to 45-49% in others; highest rates continue to be among INs, though a large increase in OP MRSA is apparent (due to emergence of CA-MRSA); ceftobiprole activity against MRSA remained consistent across all regions and evaluated patient locations; and given the prevalence of MRSA in most regions of the United States, the advent of a novel cephalosporin such as ceftobiprole with high potency against MRSA, is of great interest.

This study was supported by Ortho-McNeil-Janssen Pharmaceuticals, Inc.