Rat Microvascular Model is Tolerant to Technical Errors.

BACKGROUND: Extensive studies have been conducted using the rat model to understand the potential technical errors that lead to anastomotic failure. However, current literature indicates that the rat model has excellent tolerance to diverse errors committed by microsurgeons. The error-investigating rat model is often created by one or two experienced surgeons, and only one isolated technical error is examined. These biases may potentially cause limitations of the results from previous studies. Meanwhile, venous anastomoses have rarely been investigated in previous literature. Therefore, it is important to elucidate this topic with a more comprehensive study design. METHODS: Ninety-four arterial and 94 venous anastomoses on Sprague-Dawley rat femoral vessels that were performed by 47 microsurgeons who participated in the microsurgery course at the Columbia University and the University of Thessaloniki were evaluated. In total, 10 technical errors were examined: (1) disruption of suture line, (2) back-wall stitch, (3) oblique stitch, (4) wide bite, (5) partial thickness bite, (6) unequal suture distance, (7) tear in vessel wall, (8) excessively tight suture, (9) suture threads in lumen, and (10) large edge overlap. The frequency of each error committed, and the 30-minute postoperative patency was also recorded. The underlying causal relationship between these errors, potential interaction, and the short-term anastomosis patency was analyzed statistically. RESULTS: Only the back-wall stitch was found to have a significant causal effect on arterial anastomosis failure (p < 0.001). Back-wall stitch, wide bite, and partial thickness bite significantly impact venous anastomosis patency (p < 0.001). No other statistically significant result was found. CONCLUSION: Overall, the rat model is highly resilient to various technical errors despite these mistakes being often considered clinically unacceptable. Therefore, researchers need to consider the resilience of the rat model when designing and analyzing future studies. In addition, microsurgery instructors should focus on individual stitch quality rather than the final patency.

The Benefits of Expert Instruction in Microsurgery Courses.

BACKGROUND: Microsurgery requires repeated practice and training to achieve proficiency, and there are a variety of curriculums available. This study aims to determine the importance of an expert instructor to guide students through procedures. We compared student proficiency across two microsurgery courses: one with (Columbia University, United States [CU] cohort) and one without a dedicated microsurgery instructor (University of Thessaloniki, Greece [UT] cohort). METHODS: Students were divided into two cohorts of 22 students (UT cohort) and 25 students (CU cohort). Student progress was evaluated by examining patency (lift-up and milking tests), anastomotic timing, and quality (Anastomosis Lapse Index [ALI]) of end-to-end arterial and venous anastomoses on day 1 and again on day 5. Chi-squared tests evaluated patency immediately and 30 minutes postoperation. t-Tests evaluated anastomotic timing and ALI scores. p-Values < 0.05 were considered significant. RESULTS: We evaluated progress within and between each cohort. Within the CU cohort, the quality of the arterial and venous anastomosis improved, respectively (by 54%, p = 0.0059 and by 43%, p = 0.0027), the patency of both the arterial and venous anastomosis improved, respectively (by 44%, p = 0.0002 and by 40%, p = 0.0019), and timing of arterial and venous anastomosis reduced respectively (by 36%, p = 0.0002 and by 33%, p = 0.0010). The UT cohort improved the quality of their arterial anastomoses (by 29%, p = 0.0312). The UT cohort did not demonstrate significant improvement in the other above-mentioned parameters. The CU cohort improved materially over the UT cohort across categories of quality, patency, and timing. CONCLUSION: There are clear benefits of an expert instructor when examining the rate of progress and proficiency level attained at the conclusion of the course. We suggest students who are seeking to maximize proficiency in microsurgical procedures enroll in courses with an expert instructor.

Pharmacists and transitions of care from emergency department to home.

OBJECTIVES: To determine the impact of a pharmacist-led telephone outreach program among patients discharged from the emergency department (ED) to home. STUDY DESIGN: We conducted a randomized controlled study from February to November 2019 at a tertiary care academic medical center. METHODS: At ED discharge, participants were randomly assigned to usual care (controls) or usual care plus the pharmacist's review (intervention group). Eligible individuals included those being discharged from the ED to home with 8 or more medications. A pharmacist telephoned patients in the intervention group within 48 to 96 hours after ED discharge. The medications in the patient's record from the ED were compared with what the patient was taking at home. Discrepancies were communicated to the primary provider via fax or telephone. The primary outcome was overall health care utilization including unplanned hospital readmissions or ED visits within 30 days of discharge. The effect of the intervention on the number of acute events was analyzed using a Poisson regression model adjusting for relevant baseline characteristics. RESULTS: Of 90 eligible participants, 45 patients each were in the intervention and control groups. A total of 26 patients (58%) in the intervention group were reached, and 56 interventions were provided by the pharmacists. There was no significant difference between groups for overall health care utilization (adjusted risk ratio [aRR], 1.01; 95% CI, 0.50-2.06; P = .96), hospitalizations (aRR, 0.20; 95% CI, 0.02-2.18; P = .19), and ED visits (aRR, 1.24; 95% CI, 0.56-2.79; P = .59). CONCLUSIONS: A pharmacist-led telephone outreach program conducted after ED discharge was not associated with a change in health care utilization.

Preoperative Opioid Use Results in Greater Postoperative Opioid Consumption After Thumb Basal Joint Arthroplasty.

Purpose: Thumb basal joint arthroplasty surgery is a common hand surgery after which patients often require opioids. To better understand safe opioid consumption patterns, this study sought to identify risk factors for filling a second prescription and/or prolonged opioid use (prescription over 6 months after the surgery). Preoperative opioid use was hypothesized to show an association with greater postoperative opioid use. Methods: A retrospective review of consecutive patients who underwent primary thumb basal joint arthroplasty was conducted, yielding 110 patients for analysis. Demographic and clinical data were collected. Opioid prescription data were extracted from 6 months before the surgery to 9 months after the surgery using a state prescription drug monitoring program. Bivariate and multivariate analyses were performed for filling a second opioid prescription or filling an opioid prescription over 6 months after the surgery. Results: All the patients filled their initial postoperative prescription. Of the 110 patients, 26.4% filled an opioid prescription before the surgery, 42% filled a second postoperative prescription, and 14.5% were still consuming opioids over 6 months after the surgery. Patients using preoperative opioids had 7-fold higher odds of filling a second opioid prescription and 37-fold higher odds of prolonged use. No other demographic or clinical factors, including the type of procedure or number of initial opioids prescribed, were associated with increased use of postoperative opioids. Of all the opioid prescriptions filled after the initial postoperative prescription, only 9.3% were prescribed by a surgeon's office. Conclusions: Patients who undergo thumb basal joint arthroplasty with preoperative opioid use have much greater odds of filling a second opioid prescription and prolonged use after the surgery. Low initial surgeon-provided opioid dosages did not correlate to filling a second prescription, indicating that lower initial doses are feasible. Finally, nearly all opioid-naïve patients who filled a second opioid prescription received them from providers other than a surgeon, indicating the need for greater communication with nonsurgical providers simultaneously caring for patients in the perioperative period. Type of study/level of evidence: Therapeutic III.

Aspirin May Be a Suitable Prophylaxis for Patients with a History of Venous Thromboembolism Undergoing Total Joint Arthroplasty.

BACKGROUND: In recent years, aspirin has become a popular agent for venous thromboembolism (VTE) prophylaxis following total joint arthroplasty (TJA). Yet patients with a history of VTE are often given more aggressive prophylactic agents because of their increased baseline risk. The purpose of this study was to assess whether aspirin is an effective prophylactic agent in patients with a history of VTE. METHODS: This was a single-institution, retrospective cohort study. The electronic clinical records of 36,333 patients undergoing TJA between 2008 and 2020 were reviewed. Data on demographic characteristics, comorbidities, intraoperative factors, and postoperative complications were collected. A propensity score-matched analysis was performed, as well as a multivariate regression analysis to account for confounders. RESULTS: Of the 36,333 patients undergoing TJA, 1,087 patients (3.0%) had a history of VTE and were not receiving chronic non-aspirin. The risk for subsequent VTE was significantly higher (p = 0.03) in patients with a history of VTE (1.4%) compared with patients without prior VTE (0.9%). However, the incidence of VTE was not significantly lower (p = 0.208) in patients with a history of VTE who received aspirin (0.4%) compared with patients who received other VTE prophylaxis (1.5%). Propensity score matching showed no difference in VTE rates between the 2 groups (2.2% compared with 0.55%; p = 0.372). In a regression analysis accounting for VTE risk, the administration of aspirin was not associated with an increased risk for subsequent VTE (adjusted odds ratio, 0.32 [95% confidence interval, 0.02 to 1.66]; p = 0.274). CONCLUSIONS: Our findings suggest that, although patients with a history of VTE have an increased baseline risk for subsequent VTE, aspirin may be a suitable VTE prophylaxis in this group of patients. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

The Use of Cement and Tourniquet During Total Knee Arthroplasty Does Not Increase the Risk of Venous Thromboembolism Postoperatively.

Background: Venous thromboembolism (VTE) is a severe complication of total knee arthroplasty (TKA). Cementation and the use of tourniquet during TKA have both been hypothesized to be risk factors of VTE. The purpose of our study was to determine if either of these surgical factors increases the risk of VTE in patients undergoing TKA. Methods: A single-institution, retrospective study was conducted, consisting of 16,972 patients undergoing a primary or revision TKA from 2008 to 2020. Of the total, 1020 patients were excluded from the tourniquet analysis as tourniquet data were unavailable. Clinical records were consulted to identify demographics, surgical variables, and outcomes. Queries of clinical notes and phone-call logs were conducted to capture VTE events following discharge. Statistical analysis consisted of univariate analysis, regression analysis, and propensity score matching. Results: Compared to patients who did not receive tourniquet, the patients with tourniquet did not demonstrate a significantly higher rate of VTE in the univariate analysis (1.00 vs 1.31, P = .132). Propensity score analysis also showed no difference between the 2 cohorts (1.10 vs 0.85, P = .306). Cemented patients similarly did not demonstrate an increased risk of VTE in either the univariate (1.26 vs 1.22, P = .895) or propensity score analysis (1.42 vs 1.26, P = .710) compared to cementless patients. Regression analysis, looking at the interaction between cement and tourniquet with VTE risk as the dependent variable, revealed neither to be risk factors for VTE (odds ratio 1.38, 95% confidence interval 0.63-3.08, P = .426). Conclusions: In our cohort, neither tourniquet nor cement was a significant risk factor for VTE following TKA.

Multiple Opioid Prescribers During the Perioperative Period Increases Opioid Consumption Following Upper Extremity Surgery: A Multicenter Analysis.

Background Opioid prescribing practices have been an area of interest for orthopedic surgeons in the wake of the opioid epidemic. Previous studies have investigated the effects of a multitude of patient-specific risk factors on prolonged opioid use postoperatively. However, to date, there is a lack of studies examining the effects of multiple prescribers during the perioperative period and their potential contribution to prolonged opioid use postoperatively. This study aimed to investigate if multiple unique opioid prescribers perioperatively predispose patients to prolonged opioid use following upper extremity surgery. Second, we compared opioid prescribing patterns among different medical specialties. Methodology This retrospective study was conducted at three academic institutions. Between April 30, 2018, and August 30, 2019, 634 consecutive patients who underwent one of three upper extremity procedures  were included in the analysis: carpal tunnel release (CTR), basal joint arthroplasty (BJA), or distal radius fracture open reduction and  internal fixation (DRF ORIF). Prescription information was collected using the state Prescription Drug Monitoring Program (PDMP) online database  from a period of three months preoperatively to six months postoperatively. A Google search was performed to group prescriptions by medical specialty.  Dependent outcomes included whether patients filled an additional opioid prescription postoperatively and prolonged opioid use (defined as opioid use three to six months postoperatively). Results In total, 634 patients were identified, including 276 CTRs, 217 DRF ORIFs, and 141 BJAs. This consisted of 196 males (30.9%) and 438 females (69.1%) with an average age of 59.4 years (SD: 14.7 years). By six months postoperatively, 191 (30.1%) patients filled an additional opioid prescription, and 89 (14.0%) experienced prolonged opioid use. In total, 235 (37.1%) patients had more than one unique opioid prescriber during the study period (average 2.5 prescribers). Patients with more than one unique opioid prescriber were significantly more likely to have received overlapping opioid prescriptions (15.7% vs. 0.8%, p<.001), to have filled an additional opioid prescription postoperatively (63.8% vs 10.3%, p<.001), and to have experienced prolonged opioid use postoperatively (35.3% vs 1.5%, p<.001) compared to patients with only one opioid prescriber. Patients with multiple unique prescribers filled more opioid prescriptions compared to those with a single prescriber (2.8 refills vs 1.8 refills, p=.035). Within six months postoperatively, 71.4% of opioid refills were written by non-orthopedic providers. Opioid refills written by non-orthopedic prescribers were written for a significantly greater number of pills (68.4 vs. 27.9, p<.001), for a longer duration (22.2 vs. 6.2 days, p<.001), and for larger total morphine milligram equivalents per prescription (831.4 vs. 169.8, p<.001) compared to those written by orthopedic prescribers. Conclusions Patients with multiple unique opioid prescribers during the perioperative period are at a higher risk for prolonged opioid use postoperatively. Non-orthopedic providers were the highest prescribers of opioids postoperatively, and they prescribed significantly larger and longer prescriptions. Our findings highlight the value of utilizing PDMP databases to help curtail opioid overprescription and potential adverse opioid-related outcomes following upper extremity surgery.

Tetanus Toxin Fragment C: Structure, Drug Discovery Research and Production.

Tetanus toxoid (TTd) plays an important role in the pharmaceutical world, especially in vaccines. The toxoid is obtained after formaldehyde treatment of the tetanus toxin. In parallel, current emphasis in the drug discovery field is put on producing well-defined and safer drugs, explaining the interest in finding new alternative proteins. The tetanus toxin fragment C (TTFC) has been extensively studied both as a neuroprotective agent for central nervous system disorders owing to its neuronal properties and as a carrier protein in vaccines. Indeed, it is derived from a part of the tetanus toxin and, as such, retains its immunogenic properties without being toxic. Moreover, this fragment has been well characterized, and its entire structure is known. Here, we propose a systematic review of TTFC by providing information about its structural features, its properties and its methods of production. We also describe the large uses of TTFC in the field of drug discovery. TTFC can therefore be considered as an attractive alternative to TTd and remarkably offers a wide range of uses, including as a carrier, delivery vector, conjugate, booster, inducer, and neuroprotector.

Video-Assisted Simulation Training in Burn Management: A Comparative Cohort Study on the Assessment of Technical and Non-technical Competencies.

BACKGROUND: Written material remains one of the most common methods of education, however the current generation of learners may benefit from additional different media. In our study, we aim to quantify the effects of an innovative video instruction on subsequent resident performance in a burn patient simulation. METHODS: Following IRB approval, 60 Plastic Surgery residents were randomly assigned to two groups. The control group ("non-video" group) (n = 30) was given only written material as preparation. The experimental group ("video" group) (n = 30) was provided access to video training materials in addition to the written material on technical and non-technical skills. Their videotaped performances on simulation were evaluated by a blinded surgical faculty member. The comparison of variables between the two groups was performed using a Mann-Whitney test for non-normal distributions of quantitative variables, and Fisher's Exact Probability test for qualitative data. Statistical significance was set at p < 0.05. RESULTS: Compared to the non-video group, the video group achieved significantly higher scores in the technical skills of assessment of breathing (p = 0.015), disability (p = 0.023), and exposure (p = 0.005) and in the non-technical skills of decision-making (p = 0.035). CONCLUSIONS: In residents participating in burn patient simulations, video training in advance of the simulation significantly improved their assessments of breathing, disability, and exposure as well as decision-making. Our video is a valuable tool to enhance trainees' technical and non-technical competencies in managing burn patient simulations.

Superiority of living animal models in microsurgical training: beyond technical expertise.

BACKGROUND: Many studies are investigating the role of living and nonliving models to train microsurgeons. There is controversy around which modalities account for the best microsurgical training. In this study, we aim to provide a systematic literature review of the practical modalities in microsurgery training and compare the living and nonliving models, emphasizing the superiority of the former. We introduce the concept of non-technical skill acquisition in microsurgical training with the use of living laboratory animals in the context of a novel proposed curriculum. METHODS: A literature search was conducted on PubMed/Medline and Scopus within the past 11 years based on a combination of the following keywords: "microsurgery," "training," "skills," and "models." The online screening process was performed by two independent reviewers with the Covidence tool. A total of 101 papers was identified as relevant to our study. The protocol was reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS: Living models offer the chance to develop both technical and non-technical competencies (i.e., leadership, situation awareness, decision-making, communication, and teamwork). Prior experience with ex vivo tissues helps residents consolidate basic skills prior to performing more advanced techniques in the living tissues. Trainees reported a higher satisfaction rate with the living models. CONCLUSIONS: The combination of living and nonliving training microsurgical models leads to superior results; however, the gold standard remains the living model. The validity of the hypothesis that living models enhance non-technical skills remains to be confirmed.Level of evidence: Not ratable.

Smoothing the steep microsurgery learning curve: considering alternative suture sizes for early-stage microsurgery training with in vivo rat models.

BACKGROUND: Laboratory microsurgery training using invivo rat models is essential for clinical operation. However, challenges existin a structured training course when students transition from a non-livingmodel exercise to a living one. In the present article, we first demonstratethis steep learning curve in early-stage microsurgery training. We then proposethe potential solution of using various sizes of sutures for different trainingpurposes. METHODS: Twoseparate preliminary studies were included. First, we reviewed the records of25 students enrolled in our basic microsurgery training course. Each studentcompleted exercises in a non-living model before graduating to a live animalmodel where their performance on end-to-end arterial and venous anastomoses wasevaluated. Second, we examined the feasibility of different suture sizes in amillimeter microvascular anastomosis. Four groups of identical procedures inrat femoral artery were completed using sutures from 8-0 to 11-0. Patency rateand mean blood flow at 60 min post-op were measured and compared. RESULTS: Thirty-minute patency rates for firstarterial and venous anastomoses were 18/25 and 14/25. Those students who hadnon-patent anastomoses spent significantly longer time than those who hadpatent ones (p<.05). For varioussuture sizes, all groups achieved a 100% patency rate. No significantdifferences were found between the mean blood flow volume at 60 min post-op (p>.05). CONCLUSIONS: Steep learning curve existed in the early-stagemicrosurgery training when transitioning from non-living to living exercisemodels. The feasibility of using various suture sizes in millimeter anastomosismay be a potential solution for instructors to ease this steep learning curve.Level of Evidence: Not gradable.

Blood transfusions increase the risk for venous thromboembolism events following total joint arthroplasty.

The association between blood transfusions and thromboembolic events (VTE) following total joint arthroplasty (TJA) remains debatable. Using contemporary institutional data, this study aimed to determine whether blood transfusions increase the risk of VTE following primary and revision TJA. This was a single institution, retrospective cohort study. The clinical records of all patients (n = 34,824) undergoing primary and revision TJA between 2009 and 2020 were reviewed. Demographic variables, co-morbidities, type of chemoprophylaxis and intraoperative factors such as use of tranexamic acid were collected. Clinical notes, hospital orders, and discharge summaries were reviewed to determine if a patient received a blood transfusion. Comprehensive queries utilizing keywords for VTE were conducted in clinical notes, physician dictations, and patient-provider phone-call logs. Propensity score matching as well as adjusted mixed models were performed. After adjusting for various confounders, results from regression analysis showed a significant association between allogenic blood transfusions and risk for developing VTE following primary and revision TJA (OR 4.11, 95% CI 2.53-6.69 and OR 2.15, 95% CI 1.12-4.13, respectively). While this strong association remained significant for PE in both primary (p < 0.001) and revision (p < 0.001) matched cohorts, it was no longer statistically significant for DVT (p = 0.802 and p = 0.65, respectively). These findings suggest that the risk of VTE is increased by approximately three-folds when blood transfusions are prescribed. This association was mainly due to higher symptomatic PE events which makes it even more worrisome. Surgeons should be aware of this association, revisit criteria for blood transfusions and use all means available in the perioperative period to optimize the patients and avoid transfusion.

Outpatient parenteral antimicrobial therapy today.

Since its introduction in the 1970s, outpatient parenteral antimicrobial therapy (OPAT) has become a standard modality for patients with many infections requiring long-term intravenous antibiotic therapy. Delivery of OPAT may occur in physicians' offices, hospital clinics, specialized infusion centers, and currently most often, patient's homes, often self-administered. Patients are selected for OPAT by physicians familiar with both the course of their infections, their personal suitability for outpatient care, and the availability of reimbursement. OPAT is reportedly safe, effective, practical, and cost-effective. An OPAT Outcomes Registry contains information from >11,000 antibiotic courses administered from 1997 through 2000. Although a number of studies are purported to analyze the economic impact of OPAT on health care, a comprehensive, clinical outcomes-based pharmacoeconomic analysis, as described here, has, to our knowledge, yet to be done.

A disease model descriptive of progression between chronic obstructive pulmonary disease exacerbations and community-acquired pneumonia: roles for underlying lung disease and the pharmacokinetics/pharmacodynamics of the antibiotic.

Patients with chronic obstructive pulmonary disease (COPD) may progress to community-acquired pneumonia (CAP), but there has been no formal study of the factors responsible. We studied the influence of severity of underlying lung disease, pathogen characteristics and the ratio of the area under the concentration-time curve from 0-24h to minimum inhibitory concentration (AUC24/MIC), i.e. the area under the inhibitory curve (AUIC), during the progression from acute exacerbation of chronic bronchitis (AECB) in COPD to CAP. The model parameters were derived from a multinational database of 3885 patients with AECB or CAP (April 1996 to July 2006). Patients with underlying COPD were evaluated in two separate analyses: infection progression between COPD and CAP within Global Initiative for Chronic Obstructive Lung Disease (GOLD)-like grouping (GLG); and distribution of pathogen by GLG, CAP and AECB. Secondary analyses examined the impact of target AUIC attainment on progression to CAP for Streptococcus pneumoniae. The relative impact of GLG and AUIC were modelled in multivariate logistic regression for S. pneumoniae. Progression to CAP linked directly with GLG I/II, III and IV (18.3%, 31.7% and 48.9%, respectively; P < 0.001). Progression to CAP was strongly associated with S. pneumoniae (57.3%), whilst other pathogens were predominant in AECB that did not progress to CAP (61.7%) (P = 0.002). AUIC > or = 100 was associated with AECB (65.1%) and AUIC < 100 with CAP (91.7%) (P < 0.001). In conclusion, the frequency of progression to CAP increases directly with GLG. For S. pneumoniae, achieving an AUIC > or =100 can attenuate progression, regardless of GLG. Thus, AUIC > or = 100 appears to be a viable antibiotic selection strategy to protect patients with S. pneumoniae from developing CAP.

Clinical and economic impact of a diabetes clinical pharmacy service program in a university and primary care-based collaboration model.

OBJECTIVE: To provide program methodology and outcomes data identifying the impact of clinical pharmacy services (CPSs) in patients with type 2 diabetes. DESIGN: Longitudinal pre-post cohort study. SETTING: Regional primary care group in Buffalo, NY, during 2006-2007. PATIENTS: Patients with type 2 diabetes identified by their primary care providers were referred to the MedSense program; a pharmacist-led, patient-centered pharmacotherapy management program developed through university collaboration with a regional primary care physician group. INTERVENTIONS: Education, clinical assessments, provider recommendations, and longitudinal follow-up of treatment goals provided by MedSense pharmacists. MAIN OUTCOME MEASURES: Clinical outcomes were followed for 1 year from the index date for primary diabetes endpoints (glycosylated hemoglobin and fasting plasma glucose) and accompanying metabolic parameters (body mass index, blood pressure, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides). Economic endpoints from the payer perspective were also followed for 1 year from the index date for medical and prescription-related costs. RESULTS: Primary diabetes endpoints were significantly reduced versus baseline at the 6-month (-1.1%; P < 0.0001, -39 mg/dL; P = 0.003) and 12-month (-1.1%; P < 0.0001, -35 mg/dL; P = 0.005) assessments. Improvement rates were observed for all accompanying metabolic parameters at each assessment (range 40-64%). Geometric mean costs tended to decrease versus baseline at 6-month (-$84; P = 0.785) and 12-month (-$216; P = 0.414) assessments, despite nominal increases in diabetes and total medication costs. CONCLUSION: In this CPS model, there were initial and sustained reductions in the primary diabetes endpoints and a high rate of improvement for accompanying metabolic parameters. Concurrent with clinical improvements, total direct medical costs were reduced despite an increase in antidiabetic medication and total medication costs.

Evaluation of area under the inhibitory curve (AUIC) and time above the minimum inhibitory concentration (T>MIC) as predictors of outcome for cefepime and ceftazidime in serious bacterial infections.

The objective of this study was to evaluate the relationship of the predicted pharmacodynamic parameters 24-h area under the inhibitory curve (AUIC=area under the concentration-time curve for 24h of dosing/minimum inhibitory concentration (AUC0-24/MIC) and time above the minimum inhibitory concentration (T>MIC) with clinical and microbiological outcomes in patients with bacteraemia and sepsis treated with cefepime or ceftazidime. Pharmacokinetic and pharmacodynamic parameters were derived for 76 of 107 patients enrolled in two prospective, randomised, clinical trials comparing cefepime with ceftazidime for the treatment of sepsis with bacteraemia, lower respiratory tract infection or complicated urinary tract infection. The relationships between the pharmacodynamic parameters and outcomes were examined. Whilst no significant differences in clinical outcomes were observed between cefepime and ceftazidime, there were significant differences in the pharmacodynamic analysis. Patients with an AUIC> or =250 had significantly greater clinical cure (79% vs. 33%; P=0.002) and bacteriological eradication (96% vs. 44%; P<0.001) than patients with an AUIC<250. Patients with T>MIC of 100% had significantly greater clinical cure (82% vs. 33%; P=0.002) and bacteriological eradication (97% vs. 44%; P<0.001) than patients with T>MIC of <100%. Both microbiological and clinical cure rates were suboptimal in patients receiving cefepime or ceftazidime for the treatment of serious infections if the AUIC was <250 or T>MIC was <100%.

Pharmacoeconomics of ciprofloxacin plus metronidazole vs. piperacillin-tazobactam for complicated intra-abdominal infections.

BACKGROUND: A series of 459 hospitalized adults with complicated intra-abdominal infections participated in a randomized, double-blind, multicenter clinical trial. The present study was conducted to add a pharmacoeconomic analysis to the results. METHODS: A cost-effectiveness analysis from the perspective of the hospital provider was carried out. Decision analysis was used to illustrate outcomes and to provide a basis on which to conduct a sensitivity analysis. Cost-effectiveness ratios, representing the cost per expected successfully treated patient, were calculated to determine the most cost-effective alternative. RESULTS: Among 244 economically evaluable patients, enrolled from 34 centers in the U.S. and Canada, 131 patients received ciprofloxacin-metronidazole (75% clinical success rate), and 113 received piperacillin-tazobactam (65% clinical success rate; p = 0.06). Switch to oral antibiotics was possible for 81 patients who received ciprofloxacin-metronidazole (85% clinical success rate) and 67 piperacillin-tazobactam patients (70% clinical success rate; p = 0.027). The mean hospital cost was US$10,662 +/- 7,793 for patients in the ciprofloxacin-metronidazole group and $10,009 +/- 7,023 for patients in the piperacillin-tazobactam group (p = 0.492). Significantly lower costs were documented for patients who could be switched to oral antibiotics than for those continued on intravenous antibiotic orders ($8,684 +/- 4,120 vs. $12,945 +/- 10,204, respectively; p < 0.001). Patients with appendicitis had lower mean hospital costs than those with other infections ($7,169 +/- 3,705 vs. $12,097 +/- 8,342, respectively; p < 0.001). The cost-effectiveness ratios were $14,216:1 for patients in the ciprofloxacin-metronidazole group and $15,398:1 for patients in the piperacillin-tazobactam group. CONCLUSIONS: The mean hospital costs associated with ciprofloxacin-metronidazole were similar to those of piperacillin-tazobactam for the treatment of adults with complicated intra-abdominal infections. Lower costs were documented for patients able to be switched to oral antibiotics and for patients with appendicitis.

Once-daily cefepime versus ceftriaxone for nursing home-acquired pneumonia.

OBJECTIVES: To compare once-daily intramuscular cefepime with ceftriaxone controls. DESIGN: Double-blind study. SETTING: Six skilled nursing facilities. PARTICIPANTS: Residents aged 60 and older with nursing home-acquired pneumonia. INTERVENTION: Cultures were obtained, and patients were randomized to cefepime or ceftriaxone 1 g intramuscularly every 24 hours. MEASUREMENTS: Clinical success: cure or improvement. Cure was defined as complete resolution of all symptoms and signs of pneumonia or a return to the patient's baseline state. Improvement was defined as clear improvement but incomplete resolution of all pretherapy symptoms or signs or incomplete return to the patient's usual baseline status. Safety and pharmacoeconomics were also assessed. RESULTS: Sixty-nine patients were randomized; 61 were evaluable: (32 to cefepime, 29 ceftriaxone). Patients were predominately female (76%). They had a mean age+/-standard deviation of 85+/-6, with a mean 5.8+/-1.9 comorbidities; they had age-appropriate renal dysfunction, with a mean estimated creatinine clearance of 35+/-7 mL/min. Clinical success occurred in 78% of cefepime- and 66% of ceftriaxone-treated patients (P=.39). Fifty-seven patients (93%) were switched to oral antibiotics after 3 days. Antibiotic-related adverse events occurred in 5% of patients. Seven patients (11.5%) were hospitalized. The overall mortality rate was 8%. Mean antibiotic costs were 117+/-40 dollars for cefepime- and 215+/-68 dollars for ceftriaxone-treated patients (P<.001). Cost-effectiveness analysis of total costs showed that cefepime would cost 597 dollars and ceftriaxone 1,709 dollars per expected successfully treated patient. One- and two-way sensitivity analyses using a generic price for ceftriaxone and improving its comparative efficacy revealed that the results were robust. CONCLUSIONS: Once-daily cefepime was a cost-effective alternative to ceftriaxone for the treatment of elderly nursing home residents who developed pneumonia and did not require hospitalization.

Streptococcus pneumoniae bacteraemia: pharmacodynamic correlations with outcome and macrolide resistance--a controlled study.

There are few data on macrolide pharmacodynamics in pneumococcal infections. We evaluated pneumococcal area under the inhibitory concentration-time curve (AUIC) values at the point of hospital admission in 59 bacteraemic patients failing in the community and in 98 bacteraemic controls without macrolide exposure. The area under the 24-h concentration-time curve (AUC24) was calculated for each patient using age, weight and daily dose; using minimum inhibitory concentrations (MICs), the values of AUIC (i.e. AUC24/MIC) were then computed. Clinical and outcome information was also collected in hospital. Five of six patients who died of pneumococcal bacteraemia in hospital received azithromycin, with a mean AUIC of 8.1 prior to hospital admission. Resistant isolates were recovered in 35 (59%) macrolide failures and in only 28 (29%) controls (P=0.001). Azithromycin AUICs averaged 10 in failure patients and 17 in controls. For clarithromycin and erythromycin, the mean AUIC values in failures were 31 and 53, respectively, and the AUIC in controls was >100. Low AUIC values against Streptococcus pneumoniae precede macrolide failures in the community. Patient factors do not predict these outcomes and thus the most likely explanation for macrolide failure in the community is inadequate macrolide activity in patients who receive these antibiotics for treatment of organisms that are not sufficiently susceptible.