Ceftaroline fosamil for the treatment of Gram-positive endocarditis: CAPTURE study experience.

BACKGROUND: The clinical experience of ceftaroline fosamil (CPT-F) therapy for Gram-positive infective endocarditis is reported from CAPTURE, a retrospective study conducted in the USA. METHODS: Data, including patient demographics, medical history, risk factors, microbiological aetiology and clinical outcomes, were collected by review of patient charts between September 2013 and February 2015. RESULTS: Patients (n=55) with Gram-positive endocarditis were treated with CPT-F. The most common risk factors were intravascular devices (43.6%), diabetes mellitus (40.0%) and injection drug use (38.2%). The most commonly isolated pathogens were meticillin-resistant Staphylococcus aureus (MRSA; 80%), meticillin-susceptible S. aureus (MSSA; 7.3%) and coagulase-negative staphylococci (7.3%). CPT-F was given as first-line therapy in 7.3% of patients and as second-line or later therapy in 92.7% of patients, and as monotherapy in 41.8% of patients and as concurrent therapy in 58.2% of patients. Clinical success was observed in 82.6% (19/23) of patients treated with CPT-F as monotherapy. In patients treated with CPT-F as first-line therapy or second-line or later therapy, 75.0% (3/4) and 70.6% (36/51) achieved success, respectively. Clinical success was observed in 77.3% (34/44) of patients with MRSA and 25% (1/4) of patients with MSSA. Two patients discontinued treatment with CPT-F due to an adverse event. CONCLUSIONS: CPT-F treatment was associated with a high rate of clinical success in patients with Gram-positive infective endocarditis, including those with risk factors and infections caused by MRSA. A high rate of clinical success was observed in patients treated with CPT-F used as first- line therapy or second-line or later therapy, or as monotherapy or in combination with other antibiotics.

Use of Ceftaroline Fosamil in Osteomyelitis: CAPTURE Study Experience.

BACKGROUND: Osteomyelitis is often challenging to treat. This analysis examined the clinical experience of patients with gram-positive osteomyelitis treated with ceftaroline fosamil in the phase 4 Clinical Assessment Program and Teflaro® Utilization Registry (CAPTURE) study. METHODS: Data including patient demographics, past illnesses, risk factors, disease characteristics, antibiotic use, pathogens isolated, and clinical outcome were collected between September 2013 and February 2015 by review of randomly ordered patient charts from participating sites in the United States. Clinical success was defined as discontinuation of ceftaroline fosamil following clinical cure with no further need for antibiotics or clinical improvement with switch to another antibiotic treatment. RESULTS: A total of 150 patients with gram-positive osteomyelitis were treated with ceftaroline fosamil. Most patients (117/150; 78.0%) were treated with 600 mg ceftaroline fosamil per dose; 143/150 patients (95.3%) received a dose every 12 h. The majority (89/150 patients; 59.3%) had been previously diagnosed with diabetes mellitus or peripheral arterial disease. Osteomyelitis was associated with hardware in 32/150 patients (21.3%). Methicillin-resistant and methicillin-susceptible Staphylococcus aureus (MRSA; MSSA) were the most commonly isolated pathogens, observed in 93/150 (62.0%) and 21/150 (14.0%) patients, respectively. Clinical success with ceftaroline fosamil therapy was observed in 139/150 (92.7%) patients overall, 81/89 (91.0%) patients with diabetes or peripheral arterial disease, and 18/20 (90.0%) patients who had hardware implanted before ceftaroline fosamil therapy (none had hardware removed during therapy). Patients who received prior antibiotic therapy or ceftaroline fosamil as monotherapy experienced clinical success rates of 93.9% (107/114) and 91% (91/100), respectively. Among patients who received concurrent antibiotic therapy, the clinical success rate was 96.0% (48/50). Patients who were infected with MRSA or MSSA had clinical success rates of 92.5% (86/93) and 100% (21/21), respectively. A total of 2/150 (1.3%) patients discontinued ceftaroline fosamil therapy because of adverse events. CONCLUSIONS: Clinical success rates with ceftaroline fosamil were high in patients with gram-positive osteomyelitis, including those with diabetes or peripheral arterial disease and those with MRSA or MSSA.

Clinical Outcomes in Patients With Gram-Negative Infections Treated With Optimized Dosing Cefepime Over Various Minimum Inhibitory Concentrations.

BACKGROUND: The Clinical and Laboratory Standards Institute (CLSI) revised cefepime interpretive criteria, introducing the susceptible dose-dependent category for Enterobacteriaceae with a minimum inhibitory concentration (MIC) of 4 to 8 µg/mL in 2014. Limited clinical data support these new categories. This study compares outcomes of patients treated with standard and high-dose cefepime across various MICs. METHODS: We retrospectively reviewed cases of pneumonia or bacteremia caused by gram-negative organisms treated with adequate doses of cefepime for ≥48 hours. Outcomes were compared for MICs of ≤2 (low), 4 (medium), and 8 µg/mL (high). The primary end point was clinical failure, the secondary end point was microbiological failure. RESULTS: Ninety cases met the inclusion criteria: 46, 25, and 19 patients with low, medium, or high MIC, respectively. Multivariate logistic regression revealed that the medium (odds ratio [OR]: 9.13, P < .01) and high (OR: 6.79, P = .01) MIC groups had increased clinical failure. CONCLUSION: Cefepime therapy, even at CLSI-recommended doses, had an increased risk of clinical failure for gram-negative pathogens with MICs of 4 or 8 µg/mL. This finding suggests that higher dosing regimens (2 g every 8 hours or 1 g every 6 hours) may be necessary to treat serious gram-negative infections with elevated MICs.

Predicting the risk of nephrotoxicity in patients receiving colistimethate sodium: a multicentre, retrospective, cohort study.

OBJECTIVES: With increasing rates of infections caused by MDR Gram-negative organisms, clinicians resort to older agents such as colistimethate sodium (CMS) despite a significant risk of nephrotoxicity. Several risk factors for CMS-associated nephrotoxicity have been reported, but they have yet to be validated. We compared the performance of published mathematical models in predicting the risk of CMS-associated nephrotoxicity. METHODS: In a multicentre, retrospective, cohort study, adult patients (≥18 years of age) were evaluated from five large academic medical centres in the USA. Patients with normal renal function (baseline serum creatinine ≤1.5 mg/dL) who received intravenous CMS for ≥72 h were followed for up to 30 days. The development of nephrotoxicity was as defined by the RIFLE criteria. Each published model was conditioned using patient-specific variables to predict the risk of nephrotoxicity. The predictive performance of the models was evaluated using the observed-to-expected (O/E) ratio. The most significant cut-off threshold for stratifying patients into high and low risk of nephrotoxicity was identified using classification and regression tree analysis. RESULTS: A total of 106 patients were examined (mean age 53.3 ±â€Š14.9 years, 66% male); the overall observed nephrotoxicity rate was 52.8%. We identified a simple model demonstrating reasonable overall nephrotoxicity risk assessment [O/E ratio of 1.07 (95% CI = 0.81-1.39)] and high sensitivity (92.9%) in predicting nephrotoxicity development in patients on CMS therapy. CONCLUSIONS: We identified a model that could be incorporated into patient management strategies to reduce the risk of nephrotoxicity in patients requiring CMS therapy.

Ceftaroline fosamil as first-line versus second-line treatment for acute bacterial skin and skin structure infections (ABSSSI) or community-acquired bacterial pneumonia (CABP).

The Clinical Assessment Program and Teflaro(®) Utilization Registry (CAPTURE) is a multicenter registry study of acute bacterial skin and skin structure infection (ABSSSI) and community-acquired bacterial pneumonia (CABP) patients treated with ceftaroline fosamil in the US. Data for this analysis were collected between August 2011 and February 2013 at US study centres by randomly ordered chart review. Clinical success rates among ABSSSI patients were >81% when ceftaroline fosamil was used as first- or second-line therapy, including monotherapy and concurrent therapy. Among CABP patients, clinical success rates were >77% among first-line and second-line patients and patients who received first-line concurrent therapy or second line monotherapy or concurrent therapy. For CABP patients treated with ceftaroline fosamil as first-line monotherapy, the clinical success rate was 70%. Ceftaroline fosamil is an effective treatment option for patients with ABSSSI or CABP with similar clinical success rates when used as first-line or second-line treatment.

Significant publications on infectious diseases pharmacotherapy in 2014.

PURPOSE: The most important articles on infectious diseases (ID) pharmacotherapy published in the peer-reviewed literature in 2014, as nominated and selected by panels of pharmacists and others with ID expertise, are summarized. SUMMARY: Members of the Houston Infectious Diseases Network were asked to nominate articles published in 2014 from prominent peer-reviewed journals that were felt to have a major impact in the field of ID pharmacotherapy. A list of 19 nominated articles on general ID-related topics and 9 articles specifically related to human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS) was compiled. In a national online survey, members of the Society of Infectious Diseases Pharmacists (SIDP) were asked to select from the list 10 general ID articles believed to have made a significant contribution to the field of ID pharmacotherapy and 1 article contributing to HIV/AIDS pharmacotherapy. Of the 291 SIDP members surveyed, 134 (46%) and 56 (19%) participated in the selection of general ID-related articles and HIV/AIDS-related articles, respectively. The 11 highest-ranked papers (10 general ID-related articles, 1 HIV/AIDS-related article) are summarized here. CONCLUSION: With the vast number of articles published each year, it is difficult to remain up-to-date on current, significant ID pharmacotherapy publications. This review of significant publications in 2014 may be helpful by lessening this burden.

Lower antibiotic costs attributable to clinical microbiology rounds.

OBJECTIVE: At our institution, our microbiologist, pharmacist, and infectious disease (ID) team meet to discuss ID patients, and this meeting is referred to as microbiology rounds. We hypothesized that our microbiology rounds reduce antibiotic costs. The study involved a review of 80 patients with an ID consultation order at each of the 3 hospitals: hospital A (HA) (only HA has microbiology rounds), hospital B (HB), and hospital C (HC). Of this population, we included patients with a positive blood culture. Thirty-six patients who met the above criteria were included in the study. The average antibiotic cost/patient/day at HA, HB, and HC were $66.0, $123, and $109, respectively. Also, we found that change in antibiotics was appropriate when compared to the final microbiology results in 90%, 44%, and 40% of the time at HA, HB, and HC, respectively. Herein, we found an association between conducting microbiology rounds and reduction of antibiotic cost.

Ceftaroline fosamil for the treatment of community-acquired bacterial pneumonia in the intensive care unit.

The Clinical Assessment Program and Teflaro(®) Utilization Registry (CAPTURE) is a multicenter study evaluating the clinical use of ceftaroline fosamil in patients with community-acquired bacterial pneumonia (CABP) or acute bacterial skin and skin structure infection. Data were collected between August 2011 and February 2013, from 398 evaluable patients receiving treatment at 33 sites in the USA. This manuscript presents data collected from patients with CABP who received care in an intensive care unit (ICU) or in general medical wards (35% and 64% of evaluable patients, respectively). The majority of ICU and general medical ward patients had underlying comorbidities (78% and 74%, respectively), with structural lung disease being the most common (42% in the ICU and 40% in general medical wards). Patients admitted to the ICU had a longer duration of stay, a longer duration of symptoms before treatment, and a longer duration of ceftaroline fosamil therapy than did general medical ward patients. Most patients treated in the ICU and in general medical wards were given ceftaroline fosamil as second-line therapy (87% and 80%, respectively). The overall rate of clinical success for patients treated with ceftaroline fosamil was 68% in the ICU and 85% in the general medical wards. Clinical success for patients receiving ceftaroline fosamil as a second-line agent was 84% in the ICU and 86% in general medical wards. These findings indicate that ceftaroline fosamil is a viable treatment option for CABP, both in the ICU and in general medical wards.

Cefepime free minimum concentration to minimum inhibitory concentration (fCmin/MIC) ratio predicts clinical failure in patients with Gram-negative bacterial pneumonia.

Cefepime is an antibiotic commonly used in nosocomial infections. The objective of this study was to elucidate the relationship between cefepime exposure and clinical outcome in patients with Gram-negative bacterial pneumonia. A previously published population pharmacokinetic model of cefepime was validated in 12 adult patients with normal renal function by measuring plasma concentrations at steady-state. Additionally, clinical outcomes for 33 patients with Gram-negative bacterial pneumonia who received cefepime monotherapy were determined. The free minimum concentration (fCmin) to MIC ratio for each patient was determined by conditioning the validated pharmacokinetic model using patient-specific creatinine clearance (CLCr), dosing regimen and cefepime MIC of the organism isolated, and was subsequently correlated with clinical failure. Classification and regression tree (CART) analysis was used to determine the most significant drug exposure breakpoint. Mean±S.D. CLCr and cefepime Cmin in the 12 patients were 87.5±21.2mL/min and 6.2±3.8mg/L, respectively. In comparison, the Cmin predicted by the pharmacokinetic model was 5.8mg/L using a CLCr of 90mL/min. MICs of organisms ranged from 0.5mg/L to 8mg/L. Percent time free drug above MIC of 100% was achieved in 32/33 patients, but 12 patients experienced clinical failure. CART analysis determined patients with an fCmin/MIC≥2.1 had a significantly lower risk of clinical failure (OR=0.11, 95% CI 0.02-0.67; P=0.017). The fCmin/MIC ratio is a useful predictor of clinical failure in Gram-negative bacterial pneumonia. The clinical utility of fCmin/MIC in therapeutic drug monitoring should be further explored.

Significant publications on infectious diseases pharmacotherapy in 2013.

PURPOSE: The most important articles on infectious diseases (ID) pharmacotherapy published in the peer-reviewed literature in 2013, as nominated and selected by panels of pharmacists and others with ID expertise, are summarized. SUMMARY: Members of the Houston Infectious Diseases Network were asked to nominate articles published last year in prominent biomedical journals that had a major impact in the field of ID pharmacotherapy. A list of 27 nominated articles on ID-related topics in general and 26 articles specifically focused on human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS) was compiled. In a national online survey conducted in January 2014, members of the Society of Infectious Diseases Pharmacists (SIDP) were asked to select from the list those articles that they felt had made the greatest contributions to the field of ID pharmacotherapy. Of 168 SIDP members surveyed, 108 (64%) and 53 (32%) participated in the selection of ID- and HIV/AIDS-related articles, respectively. Summaries of the top-ranked articles in both categories are presented. CONCLUSION: Major topics explored in the top-ranked ID articles of 2013 include the use of cefepime for gram-negative infections due to AmpC or extended-spectrum ß-lactamase-producing Enterobacteriaceae, optimizing antibiotic therapy through the use of extended- or continuous-infusion regimens, the use of the oral integrase inhibitor dolutegravir to combat HIV disease, and new approaches to treatment of Clostridium difficile infection and enterococcal endocarditis.

Trends in multidrug-resistant gram-negative bacilli and the role of prolonged ß-lactam infusion in the intensive care unit.

Multidrug-resistant gram-negative bacilli are emerging threats in the intensive care unit setting worldwide. Extended-spectrum ß-lactamases, AmpC ß-lactamases, and carbapenem-resistant Enterobacteriaceae are increasing at an alarming rate, leaving limited therapeutic options. In addition, multidrug resistance among Pseudomonas aeruginosa and Acinetobacter baumannii has widely disseminated and become a frequent cause of nosocomial infections within many intensive care units. Therefore, resistance is increasing to all currently available antibiotics, including cephalosporins, penicillins, aztreonam, carbapenems, fluoroquinolones, and aminoglycosides. Some multidrug-resistant gram-negative bacteria remain susceptible to only a few antibiotics such as tigecycline, fosfomycin, and polymyxins. The steady trend of increasing resistance coupled with the lack of novel antibiotics targeting resistant gram-negative bacilli has forced clinicians to increasingly apply more aggressive dosing strategies, such as prolonged and continuous infusion of ß-lactam antibiotics to address the challenges associated with these difficult-to-treat pathogens. Nurses who have a thorough understanding of antibiotic resistance patterns, infection control procedures, and appropriate antibiotic use and dosing regimens, particularly the method of administration, are essential in the battle to preserve the usefulness of antibiotics and prevent further antibiotic resistance.

Activated partial thromboplastin time versus antifactor Xa heparin assay in monitoring unfractionated heparin by continuous intravenous infusion.

BACKGROUND: Unfractionated heparin (UFH) has been used clinically for 5 decades. Despite being a cornerstone of anticoagulation, UFH is limited by its unpredictable pharmacokinetic profile, which makes close laboratory monitoring necessary. The most common methods for monitoring UFH are the activated partial thromboplastin time (aPTT) and antifactor Xa heparin assay (anti-Xa HA), but both present challenges, and the optimal method to monitor UFH remains unclear. OBJECTIVE: To compare the performance of the aPTT with the anti-Xa HA for efficiency and safety of monitoring intravenous UFH infusions. METHODS: This was a single-center, retrospective, observational cohort study conducted in an 852-bed academic medical center. RESULTS: One hundred patients receiving intravenous UFH for a variety of indications were enrolled in the study; 50 were assigned to each group. The mean (SD) time to achieve therapeutic anticoagulation was significantly less in the anti-Xa HA group compared with the aPTT group (28 [16] vs 48 [26] hours, p < 0.001). In addition, a greater percentage of anti-Xa HA patients compared to aPTT patients achieved therapeutic anticoagulation at 24 hours (OR 3.5; 95% CI 1.5 to 8.7) and 48 hours (OR 10.9; 95% CI 3.3 to 44.2). Patients in the anti-Xa HA group also had more test values within the therapeutic range (66% vs 42%, p < 0.0001). A significant difference was seen between the 2 groups in the number of aPTT or anti-Xa HA tests performed per 24 hours (p < 0.0001) and number of infusion rate changes per 24 hours (p < 0.01), both favoring the anti-Xa HA group. CONCLUSIONS: Monitoring intravenous UFH infusions with the anti-Xa HA, compared to the aPTT, achieves therapeutic anticoagulation more rapidly, maintains the values within the goal range for a longer time, and requires fewer adjustments in dosage and repeated tests.