ࡱ>  bjbjVV 8<<>>===QQQ8  |Q&'&(O&O&O&' ' 'Q=/*''/*/*O&O&4ב666/*O&=O&6/*66f p6<O&Ч {Q0|Dp0|e22e<<e=T'C(^6(L(B'''4'''/*/*/*/*e'''''''''> G: Ceftaroline fosamil (Teflaro) May 2011 National Drug Monograph VA Pharmacy Benefits Management Services, Medical Advisory Panel, and VISN Pharmacist Executives The purpose of VA PBM Services drug monographs is to provide a comprehensive drug review for making formulary decisions. These documents will be updated when new clinical data warrant additional formulary discussion. Documents will be placed in the Archive section when the information is deemed to be no longer current. Executive Summary:1-3 Ceftaroline is a fifth generation cephalosporin antibacterial that received FDA approval (October 2010) for the treatment of adult patients with acute bacterial skin and skin structure infection (ABSSSI), formerly known as complicated skin and skin structure infection, and community-acquired bacterial pneumonia (CABP). Ceftaroline displays in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA), which is unique among the class of cephalosporins. It also demonstrates in vitro activity against Streptococcus pneumonia including penicillin-resistant strains. Similar to other cephalosporins, ceftaroline lacks activity against Enterococcus spp. Against most Gram-Negatives, ceftarolines spectrum of activity is comparable to ceftriaxone (ie, lacks activity Pseudomonas and Acinetobacter species). Four pivotal, Phase III clinical trials (FOCUS and CANVAS) were conducted to evaluate the efficacy and safety of ceftaroline in the treatment of CABP and ABSSSI, respectively. The study designs of FOCUS 1 and 2 were similar and aimed to establish non-inferiority in clinical cure rates of ceftaroline compared with ceftriaxone in patients with CABP. Of note, patients with a strong suspicion of MRSA pneumonia or pneumonia secondary to atypical organisms were excluded from the study. Ceftaroline demonstrated non-inferiority to ceftriaxone for the treatment of hospitalized patients with CABP and was efficacious against Streptococcus pneumonia and in a subset of patients with Streptococcus pneumonia bacteremia. The study designs of CANVAS 1 and 2 were identical and aimed to establish the non-inferiority of the clinical cure rate achieved with ceftaroline monotherapy compared with vancomycin plus aztreonam in patients with ABSSSIs. Ceftaroline monotherapy was efficacious for the treatment of cSSSI, with a clinical cure rate comparable to that of vancomycin + aztreonam. Ceftaroline was well tolerated and had a favorable safety profile, with rates of AEs and SAEs similar to those of ceftriaxone in the CABP trial. The most common adverse events noted were nausea, vomiting, diarrhea and rash. Ceftaroline, a cephalosporin with MRSA in vitro activity, has shown to be efficacious in the treatment of skin and skin structure infection and community-acquired bacterial pneumonia. Introduction The purposes of this monograph are to (1) evaluate the available evidence of safety, tolerability, efficacy, cost, and other pharmaceutical issues that would be relevant to evaluating ceftaroline for possible addition to the VA National Formulary; (2) define its role in therapy; and (3) identify parameters for its rational use in the VA. Pharmacology/Pharmacokinetics:1-3 Ceftaroline is a fifth generation cephalosporin that exerts bactericidal activity against Gram-Positive and Gram-Negative organisms. The mechanism of action is similar to other beta-lactams where it inhibits cell wall biosynthesis by binding to penicillin binding proteins (PBPs) and inhibits the transpeptidation step of peptidoglycan biosynthesis in the bacterial cell wall. Ceftaroline displays time-dependent killing and the Time above the MIC (T>MIC) is the main pharmacodynamic parameter predicting efficacy. Table 1: Pharmacokinetics of Ceftaroline at Steady-State Parameter (SD) CeftarolineMetabolismProdrug; rapidly converted by in vivo phosphatase enzymes to the microbiologically active ceftaroline that exerts bactericidal activity. Ceftaroline does not utilize the cytochrome P450 enzyme system for metabolic transformationEliminationCeftaroline and its metabolites (ceftaroline M-1) are primarily eliminated by the kidneysCmax (mcg/mL) 21.3 (4.10)Tmax (h)0.92 (0.92-1.08)AUC (mcg"h/mL)56.3 (8.90) Half-life (SD)2.66 (0.4) Protein BindingPlasma protein binding of ceftaroline is approximately 20% Microbiology:3-6 Ceftaroline displays in vitro activity against a wide-variety of Gram-Positive and Gram-Negative Organisms (Refer to Table 2). Most notably, ceftaroline displays in vitro activity against MRSA through its strong binding affinity to PBP 2a. In analysis of 2,254 MRSA isolates, approximately 5% of MRSA isolates have MICs > 1.0 g/mL and thus are resistant to ceftaroline (susceptible breakpoint for MRSA is MIC d" 1 g/mL). Ceftaroline has also shown in vitro activity against vancomycin-intermediate Staphylococcus aureus (VISA), vancomycin-resistant Staphylococcus aureus (VRSA), and daptomycin non-susceptible Staphylococcus aureus. Ceftaroline has activity against Streptococcus pneumonia including penicillin-resistant isolates, S. viridians and S. agalactiae. Similar to other cephalosporins, ceftaroline demonstrates lacks activity against Enterococcus faecalis and faecium. Ceftaroline displays in vitro activity against many Gram-Negatives including Escherichia coli, Klebsiella pneumonia, Morganella sp., Haemophilus sp., Moraxella sp., Providencia sp. and Serratia marsecens. Ceftaroline lacks activity against Pseudomonas aeruginosa and Acinetobacter sp. In addition, ceftaroline is inactivated by extended-spectrum beta lactamase (ESBL) producing and AmpC overexpressing organisms. Ceftaroline has the ability to induce AmpC enzyme production, to an extent comparable to ceftriaxone and cefotaxime, however to a lesser degree than cefoxitin. Ceftaroline has activity against some of the Gram-Positive anaerobic such as Actinomyces species, Propionibacterium species, Fusobacterium species. It lacks activity against Bacteroides and Prevotella isolates. Table 2. In vitro MIC90 (g/mL) values for Ceftaroline against select Gram-Positive and Gram-Negative clinical isolates collected (2004-2006) in United States4 : Bacteria; no. of isolatesCeftaroline MIC90 (g/mL)Staphylococcus aureus Oxacillin-susceptible (MSSA); n= 348 Oxacillin-resistant (MRSA); n= 661 0.25 1.00Coagulase-negative staphylococci Oxacillin-susceptible; n= 201 Oxacillin-resistant; n= 299 0.12 0.50Streptococcus pneumonia Penicillin susceptible; n= 202 Penicillin intermediate; n= 103 Penicillin-resistant, MIC > 2 g/mL; n= 296 0.015 0.06 0.12Enterococcus faecalis Vancomycin-susceptible; n= 157 Vancomycin-resistant; n= 25 4 4Enterococcus faecium Vancomycin-resistant; n= 26 > 16Haemophilus influenza Beta-lactamase negative; n= 199 Beta-lactamase positive; n= 101 0.015 0.03Escherichia coli Ceftazidime-susceptible; n= 345 Ceftazidime-non-susceptible; n= 63 0.5 > 16Klebsiella pneumonia Ceftazidime-susceptible; n= 210 Ceftazidime-non-susceptible; n= 66 0.25 > 16 FDA Approved Indication(s) and Off-label Uses1-3 Ceftaroline is indicated for the treatment of the infections caused by Acute bacterial skin and skin structure infections caused by susceptible Gram-Positive and Gram-Negative organisms including S. aureus (MSSA and MRSA), S. pyogenes, S. agalactiae, E. coli, K. pneumoniae, and K. oxytoca Community-acquired pneumonia caused by susceptible Gram-Positive and Gram-Negative organisms including S. pneumoniae with concurrent bacteremia, S. aureus (MSSA only), H. influenza, K. pneumonia, K. oxytoca, and E. coli. This section is not intended to promote any off-label uses. Off-label use should be evidence-based. See VA PBM-MAP and Center for Medication Safetys  HYPERLINK "http://vaww.national.cmop.va.gov/PBM/Directives%20Policies%20and%20Information%20Letters/Guidance%20on%20Off%20Label%20Prescribing.pdf" Guidance on Off-label Prescribing (available on the VA PBM intranet site only). At this time, there are no active phase 3 clinical trials being conducted with ceftaroline for other indications according to clinicaltrials.gov. The FDA labeling for acute bacterial skin and skin structure includes MRSA and MSSA while community-acquired pneumonia only includes MSSA (and not MRSA). Patients with suscepted MRSA community-acquired pneumonia were excluded in the clinical trials). Thus, potential for off-label usage may include MRSA infections such as community-acquired pneumonia and healthcare-associated pneumonia as well as coagulase-negative staphylococcal infections. Current VA National Formulary Alternatives9-10 Acute Bacterial Skin and Skin Structure Infections: Parenteral anti-MRSA agents on VANF include vancomcyin, clindamycin, daptomycin, linezolid, and tigecycline. The PBM have Recommendations for Use for daptomycin, linezolid, and tigecycline. Community-Acquired Bacterial Pneumonia: Parenteral agents on VANF include ampicillin, ampicillin-sulbactam, azithromycin (used in combination with beta-lactam), ceftriaxone, cefotaxime, and moxifloxacin. Dosage and Administration1-3 The recommended adult dosage is 600 mg administered intravenous infusion every 12 hours over 1 hour. The recommended duration of therapy for community-acquired pneumonia is 5-7 days, while a 7-14 days course is recommended for skin and soft tissue infections, depending on the extent and severity of the infection. Renal Impairment: Dosage adjustments are recommended in renal impairment (Refer to Table 3). Table 3. Dosage Adjustments in Renal Impairment Creatinine Clearance (mL/min)Ceftaroline Dosage Regimen>50No dosage adjustment necessary> 30 - < 50400 mg IV infused over 1 hour every 12 hours> 15 - < 30300 mg IV infused over 1 hour every 12 hoursEnd-stage renal disease on hemodialysisa200 mg IV infused over 1 hour every 12 hoursaCeftaroline is hemodialyzable and should be admininstered after hemodialysis on hemodialysis days Hepatic Impairment: No dosage adjustments recommended in patients with mild or moderate hepatic impairment. Efficacy1-3,7-8 Four pivotal, Phase III clinical trials (CANVAS and FOCUS) were conducted to evaluate the efficacy and safety of ceftaroline in the treatment of ABSSSIs and CABP, respectively. The study designs of CANVAS 1 and 2 trials were identical and designed to establish the non-inferiority of ceftaoline to the combination of vancomycin+aztreonam in the treatment of ABSSSIs. The study designs of FOCUS 1 and 2 trials were similar and aimed to establish the non-inferiority of ceftaroline monotherapy to ceftriaxone in the treatment of hospitalized patients with CABP. Efficacy Endpoints: CANVAS Primary outcome: Per-patient clinical cure rate at the test-of-cure visit in clinically evaluable and modified intent-to-treat populations Efficacy Endpoints: FOCUS Primary outcome: Clinical cure rate at the test-of-cure visit in Clinically Evaluable and Modified Intent-To-Treat Efficacy populations The combined analyses for CANVAS I and II are presented in Appendix A while the combined analyses for FOCUS I and II are presented in Appendix B. The primary endpoints for individual trials are listed in this section (Table 5 and Table 6). Table 5. CANVAS: Clinical Cure Rates at Test-of-Cure Ceftaroline n/N Vancomycin/Aztreonam n/N Treatment Difference (2-sided 95% CI)ABSSSI Trial 1CE288/316 (91.1%)280/300 (93.3%)-2.2 (-6.6, 2.1)MITT304/351 (86.6%)297/347 (85.6%)1.0 (-4.2, 6.2)ABSSSI Trial 2CE271/294 (92.2%)269/292 (92.1%)0.1 (-4,4, 4.5)MITT291/342 (85.1%)289/338 (85.5%)-0.4 (-5.8, 5.0) Table 6. FOCUS : Clinical Cure Rates at Test-of-Cure Ceftaroline n/N Ceftriaxone n/N Treatment Difference (2-sided 95% CI)CABP Trial 1CE194/224 (86.6%)183/234 (78.2%)8.4 (1.4, 15.4)MITT244/291 (83.8%)233/300 (77.7%)6.2 (-0.2, 12.6)CABP Trial 2CE191/232 (82.3%)165/214 (77.1%)5.2 (-2,2, 12.8)MITT231/284 (81.3%)203/269 (75.5%)5.9 (-1.0, 12.8) Summary of efficacy findings In the CANVAS phase III clinical studies, ceftaroline monotherapy was found to be safe and efficacious for the treatment of complicated skin and skin structure infections including those caused by MSSA and MRSA, with a clinical cure rate comparable to that of vancomycin plus aztreonam. The clinical cure rates with ceftaroline were similar to vancomycin plus aztreonam in patients infected with single or multiple pathogens, across infection types (including cellulitis, major abscess, and infected wound), and between patients with common comorbidities, such as diabetes mellitus and peripheral vascular disease. In the FOCUS Phase III clinical studies, ceftaroline monotherapy was efficacious in hospitalized patients with CABP caused by S. pneumonia and subset of patients with S. pneumonia bacteremia, and served as an efficacious, well-tolerated treatment, comparable to ceftriaxone. Adverse Events (Safety Data)1-3 Ceftaroline was evaluated in four controlled comparative Phase 3 clinical trials; two in ABSSSI (CANVAS 1 and 2) and two in CABP (FOCUS 1 and 2). There were 1300 adult patients who received ceftaroline 600 mg intravenously every 12 hours and 1297 patients who were treated with comparator treatments (vancomycin plus aztreonam or ceftriaxone) for a treatment period of up to 21 days. Common Adverse Events Pooled data from Phase 3 clinical trials revealed that the most common adverse events that occurred in > 2% of patients receiving ceftaroline were diarrhea, nausea and rash. No adverse events occurred in greater than 5% of patients receiving ceftaroline. Table 7: Adverse Events occurring in > 2% of Patients treated with Ceftaroline Adverse EventCeftaroline (n= 1300)Comparators (n= 1297)Diarrhea5%3%Nausea4%4%Constipation2%2%Vomiting2%2%Increased transaminases2%3%Hypokalemia2%3%Rash3%2%Phlebitis2%1%Adapted from prescribing information Other Adverse Events Additional adverse events that were reported by 1740 patients receiving ceftaroline in clinical trials (including Phase II, III and pharmacology studies) with an incidence less than 2% were anemia, neutropenia, thrombocytopenia, bradycardia, abdominal pain, pyrexia, hepatitis, hypersensitivity, anaphylaxis, Clostridium difficile colitis, hyperglycemia, hyperkalemia, dizziness, convulsions, renal failure and urticaria. Deaths and Other Serious Adverse Events (Sentinel Events) Data from the four pooled Phase 3 clinical trials showed that serious adverse events (SAEs) occurred in 98/1300 (7.5%) of patients receiving ceftaroline and 100/1297 (7.7%) of patients receiving comparator agents. The respiratory and infection system organ classes had the most incidence of SAEs. In the CANVAS trials, three patients in the ceftaroline group died due to respiratory failure, neck cancer, and cardiopulmonary insufficiency. In the FOCUS trials, two patients in the ceftaroline group died due to myocardial infarction and multiorgan disorder. Tolerability Treatment discontinuation secondary to adverse events, most commonly hypersensitivity, occurred in 35/1300 (2.7%) of patients receiving ceftaroline and 48/1297 (3.7%) of patients receiving comparator drugs. Hypersensitivity occurred at a rate of 0.3% in the ceftaroline group and 0.5% in the comparator group. Contraindications Ceftaroline is contraindicated in patients with known serious hypersensitivity (anaphylaxis and anaphylactoid reactions) to ceftaroline or any other members of the cephalosporin antimicrobial class. Warnings/Precautions Hypersensitivity Reactions: Ceftaroline, being a fifth generation cephalosporin, may demonstrate cross-sensitivity with other beta-lactams; hence, if cefatraoline is to be administered to a penicillin- or other beta-lactam-allergic patient, caution should be exercised. Clostridium difficile-associated Diarrhea (CDAD): CDAD has been reported with ceftaroline use, and should be considered in all patients who present with diarrhea following ceftaroline use. Direct Coombs Test Seroconversion: Seroconversion from a negative to a positive direct Coombs test result occurred in 120/1114 (10.8%) of patients receiving ceftaroline and 49/1116 (4.4%) of patients receiving comparator drugs in the four pooled Phase 3 trials. In the integrated analysis FOCUS 1 and 2 for CABP, 51/520 (9.8%) of ceftaroline-treated patients compared to 24/534 (4.5%) of ceftriaxone-treated patients seroconverted from a negative to a positive direct Coombs test result. No adverse reactions representing hemolytic anemia were reported in any treatment group. If anemia develops during or after treatment with ceftaroline, drug-induced hemolytic anemia should be suspected and diagnostic studies including a direct Coombs test, should be performed. If proven, the package insert recommends discontinuation of ceftaroline and provision of supportive care to the patient (i.e. transfusion) as clinically indicated. Promotion and Development of Antimicrobial-Resistant Bacteria: Ceftaroline use in the absence of a proven or strongly suspected bacterial infection is unlikely to provide any benefit to the patient and may promote the development of drug-resistant bacteria. Pregnancy: Category B Nursing: Unknown if ceftaroline is excreted in breast milk Look-alike / Sound-alike (LA / SA) Error Risk Potential As part of a JCAHO standard, LASA names are assessed during the formulary selection of drugs. Based on clinical judgment and an evaluation of LASA information from four data sources (Lexi-Comp, USP Online LASA Finder, First Databank, and ISMP Confused Drug Name List), the following drug names may cause LASA confusion: NME Drug NameLexi-CompFirst DataBankUSPISMPClinical JudgmentCeftaroline fosamil TeflaroNone NoneNone NoneNone NoneNone NoneCeftazidime None Drug Interactions Clinical drug interaction studies have not been conducted with ceftaroline. However, there is minimal potential for drug-drug interactions between ceftaroline and CYP450 substrates, inhibitors, or inducers. Acquisition Costs Table 8.Acquisition costs DrugDoseaCost ($) /Day/PatientCost ($) for 7-day course of therapyCeftarolineb600mg IV every 12 hrs$60.50$423.50Potential Alternatives for complicated skin and skin structure due to MRSAVancomycinb 1 gram IV every 12 hrs$7.74$54.18Clindamycin900mg IV every 8 hrs$26.76/premix bag $8.25/vial$187.32/premix bag $57.75/vialDaptomycinb4 mg/kg IV every 24 hrs$150.33$1,052Linezolid600mg IV every 12 hrs$132.26$928.62Tigecycline100mg load and then 50mg IV every 12 hrs$88.95$622.65Potential Alternatives for community-acquired pneumonia Ampicillin-sulbactam1.5-3gm IV every 6 hrs$19.34$135.41Cefotaxime1 gram IV every 8 hrs$3.33$23.31Ceftriaxone1 gram IV every 24 hrs$1.33$9.31Moxifloxacin 400 mg IV every 24 hrs$8.78$61.46a Dose based upon 80 kg person and normal renal function for purpose of cost analyses; bCeftaroline 600mg and 400mg vials have the same price, prices obtained June 2011 Pharmacoeconomic Analysis A pharmacoeconomic analysis of ceftaroline was not found in a review of the published literature. Conclusions Ceftaroline is a novel, broad spectrum, fifth generation cephalosporin that received FDA approval for the treatment of adult patients with acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. Unlike other cephalosporins, ceftaroline displays potent in vitro activity against MRSA through strong binding affinity to penicillin binding protein 2a. In the four phase III clinical trials, ceftaroline demonstrated similar clinical cure rates and was proven to be non-inferior to vancomycin/aztreonam and ceftriaxone for the treatment of complicated skin and skin structure infections and community acquired bacterial pneumonia, respectively. Ceftaroline lacks activity against Pseudomonas aeruginosa and inactivated by ESBL-producing and AmpC-producing organisms. References: Teflaro (ceftaroline fosamil) Package Insert. Forest Laboratories, Inc. October 27, 2010 Ceftaroline Medical Review. Center for Drug Evaluation and Research (CDER). Application Number 200327. December 2009; Pages 1-246 FDA Advisory Committee Briefing Document. Ceftaroline Fosamil for Injection in Complicated Skin and Skin Structure Infections and Community-acquired Bacterial Pneumonia NDA 200327. September 2010. Forest Research Institute, Inc. Ge Y, Biek D, Talbot GH, Sahm DF. In vitro profiling of ceftaroline against a collection of recent bacterial clinical isolates from across the United States. Antimicrob Agents Chemother. 2008;52:33983407 Jacobs MR, Good CE, Windau AR, et al. Activity of ceftaroline against recent emerging serotypes of Streptococcus pneumoniae in the United States. Antimicrob Agents Chemother. 2010;54:27162719 Housman, Kuti, Nicolau. Ceftaroline: A novel cephalosporin with methicillin-resistant Staphylococcus aureus and multidrug-resistant Streptococcus pneumoniae activity. Formulary. 2011;46:7181 Corey GR, Wilcox M, Talbot GH et al. Integrated Analysis of CANVAS 1 and 2: Phase 3, Multicenter, Randomized, Double-Blind Studies to Evaluate the Safety and Efficacy of Ceftaroline versus Vancomycin plus Aztreonam in Complicated Skin and Skin-Structure Infection. Clinical Infectious Diseases 2010;51(6):641-650 File TM, Low DE, Eckburg PB, Talbot GH, Friedland HD, Lee J, Llorens L, Critchley I, Thye D. Integrated Analysis of FOCUS 1 and FOCUS 2: Randomized, Double-Blinded, Multicenter Phase 3 Trials of the Effiicacy and Safety of Ceftaroline Fosamil vs. Ceftriaxone in Patients with Community-Acquired Pneumonia. Clinical Infectious Diseases 2010;51(12):1395-1405 Liu C. Clinical Practice Guidelines by the Infectious Diseases Society of America for the Treatment of Methicillin-Resistant Staphylococcus Aureus Infections in Adults and Children. CID 2011:52 (on-line access January 4, 2011) Mandell LA et al. Infectious Diseases Society of America/American Thoracic Society Consensus Guidelines on the Management of Community-Acquired Pneumonia in Adults. CID 2007:44 (Suppl 2) Appendix A: Summary of Phase III Complicated Skin and Soft Structure Infections (cSSSIs) Clinical Trials7 CitationCorey GR et al. Integrated Analysis of CANVAS 1 and 2: Phase 3, Multicenter, Randomized, Double-Blind Studies to Evaluate the Safety and Efficacy of Ceftaroline versus Vancomycin plus Aztreonam in Complicated Skin and Skin-Structure Infection. Clinical Infectious Diseases 2010;51(6):641-650.Study GoalsEvaluate the efficacy and safety of ceftaroline monotherapy compared to vancomycin plus aztreonam therapy for complicated skin and skin structure infections. MethodsStudy Design CANVAS 1 and CANVAS 2 (Ceftaroline versus Vancomycin in Skin and Skin-Strucure Infection) were two identical, phase III, international, multicenter, active-controlled, parallel group, randomized, double-blind, clinical trials. Study Groups: Ceftaroline (600 mg IV every 12 hours) followed by normal saline placebo Vancomycin (1000 mg IV every 12 hours) followed by aztreonam (1000 mg IV every 12 hours) Ceftaroline dose was renally adjusted to 400 mg in patients with moderate renal impairment (CrCl > 30 and < 50 ml/min). Vancomycin dose was renally adjusted based on institutional guidelines and practices. Therapy was deemed as being complete on the basis of investigator: Resolution/improvement of all signs and symptoms of infection Aztreonam/placebo was discontinued if no gram-negative pathogen was identified/suspected Study Populations: Modified intent-to-treat (MITT) Microbiological modified intent-to-treat (mMITT) Clinically evaluable (CE) Microbiologically evaluable (ME) Efficacy/Outcome Measures: Primary outcome: Per-patient clinical cure rate at the test-of-cure visit (8-15 days after last dose of study drug) in CE and MITT populations Secondary outcomes: Per-patient microbiological response Per-patient clinical and microbiological response at the test-of-cure visit Relapse and re-infection rates at the late follow-up visit (21-35 days after last dose of study drug) Data Analysis: Point estimate for primary outcome assumed to be 85% in both treatment groups; Sample size of 690 patients (345 per treatment group) were required for each study. Non-inferiority margin set at 10%; power set at 90%; nonevaluable rate of 20%CriteriaInclusion criteria: Age > 18 years cSSSI requiring initial hospitalization or treatment in an emergency department and > 5 days of intravenous antimicrobial therapy > 3 clinical signs of infection: Purulent or seropurulent drainage or discharge, erythema, fluctuance, heat or localized warmth, pain or tenderness on palpation, WBC > 10,000 cells/L, or > 10% immature neutrophils cSSSI that met either of the following criteria: Involving deep soft tissue or requiring significant surgical intervention, such as wound infection with purulent drainage or > 5cm of surrounding cellulitis, major abscess surrounded by > 2cm of cellulitis, infected ulcer, or cellulitis with surface area of > 10cm2 Cellulitis or abscess of lower extremity in patients with diabetes mellitus or documented peripheral vascular disease Exclusion criteria: Received > 24 hours of antimicrobial treatment within 96 hours before randomization, unless evidence of clinical and microbiological failure after > 48 hours of therapy Current pathogen known or suspected to be resistant to vancomycin or aztreonam CrCl < 30 mL/min cSSSI known or suspected to be caused by Pseudomonas aeruginosa or an anaerobic, fungal, parasitic, or viral pathogen Decubitus ulcer, diabetic foot ulcer, or ulcer secondary to peripheral vascular disease accompanied by osteomyelitis or requiring amputation or revascularization within 60 days Required surgical intervention that could not be performed within 48 hrs Third degree burn or burn covering > 5% of the body Human, animal or arthropod bites Necrotizing fasciitis or gangrene Endocarditis, osteomyelitis or septic arthritis Required concomitant antimicrobial therapy or high-dose corticosteroid therapyResultsEnrollment: CANVAS 1 enrolled 703 patients (February 2007 November 2007) and CANVAS 2 enrolled 699 patients (March 2007 December 2007). Demographics: Study arms had similar demographic characteristics, type and site of cSSSI, and relevant medical/surgical history. Age > 65 years, 18.1%; age > 75 years; 7.5% Predominantly white and male 3.6% of all patients had moderate renal impairment requiring dosage adjustments (CrCl > 30 and < 50 mL/min) Baseline Demographics and Patient Characteristics Ceftaroline (n = 693) Vancomycin + Aztreonam (n = 685) Age, median years (range) 48.0 (18-93) 48.0 (18-96) BMI, median (range) 26.9 (14.1-74.1) 27.4 (16.6-66.5) Duration of therapy, mean days + SD 8.3 + 3.2 8.4 + 3.3 Comorbid/Predisposing conditions, no. (%) Diabetes mellitus Peripheral vascular disease Injection drug use 122 (17.6) 93 (13.4) 46 (6.6) 120 (17.5) 93 (13.6) 59 (8.6) Bacteremia, no. (%) 29 (4.2) 26 (3.8) Prior antimicrobial tx, no. (%) 276 (39.8) 260 (38) Median infection area (cm2) 156 150 Infection type (%) Cellulitis Major abscess Infected wound Other 35.9 34.3 14.7 15.1 39.9 34.2 12.0 13.9 Isolation of MRSAa (%) 40 34 aThe MIC range (g/mL) was 0.25-2 for ceftaroline and 0.5-2 for vancomycin. Clinical Cure Rate at the Test-of-Cure Visit Cure rate, # of patients cured/total # of patients (%) Population Ceftaroline Vancomycin+ Aztreonam Difference CE (co-primary efficacy endpoint) 559/610 (91.6) 549/592 (92.7) -1.1 (-4.2 to 2.0) MITT (co-primary efficacy endpoint) 595/693 (85.9) 586/685 (85.5) 0.3 (-3.4 to 4.0) ME Gram-Positive Gram-Negative Mixed Polymicrobial 434/468 (92.7) 348/371 (93.8) 29/34 (85.3) 57/63 (90.5) 125/136 (91.9) 421/446 (94.4) 330/350 (94.3) 24/24 (100) 67/72 (93.1) 134/139 (96.4) -1.7 (-4.9 to 1.6) -0.5 (-4.1 to 3.1) -15.6 (-31.6 to -1.2) -2.6 (-13.4 to 7.2) -4.2 (-10.5 to 1.5) Clinical Response at Test-of-cure by Baseline Pathogen, mMITT Population Ceftaroline n (%) Vancomycin plus aztreonam n (%) Weighted Difference 95% CI Gram-positives 429/489 (87.7) 420/485 (86.6) 1.1 (-3.1, 5.4) S. aureus 377/425 (88.7) 356/409 (87) 1.6 (-2.8, 6.1) MSSA 221/245 (90.2) 233/258 (90.3) -0.1 (-5.5, 5.2) MRSA 155/179 (86.6) 124/151 (82.1) 4.4 (-3.4, 12.6) S. pyogenes 56/63 (88.9) 57/62 (91.9) -1.8 (-13.3, 9.5) S. agalactiae 25/27 (92.6) 19/21 (90.5) NA S. anginosus group 12/15 (80.0) 16/18 (88.9) NA S. dysgalactiae 14/14 (100) 15/17 (88.2) NA Gram-negatives 92/108 (85.2) 97/111 (87.4) -2.2 (11.7, 7.1) E. coli 21/23 (91.3) 19/21 (90.5) NA K. pneumoniae 17/18 (94.4) 14/19 (73.7) NA K. oxytoca 10/12 (83.3) 7/8 (87.5) NA M. morganii 11/12 (91.7) 5/7 (71.4) NA Clincial Cure Rates at Test-of-Cure by Demographics and Baseline Characteristics CE Population Ceftaroline (N=610) n/N (%) Vancomycin plus aztreonam (N=392) n/N (%) Weighted Difference 95% CI Diabetes Mellitus No 463/500 (92.6) 449/482 (93.2) -0.5 (-3.8, 2.8) Yes 96/110 (87.3) 100/110 (90.9) -3.5 (-12.2, 5.0) Presence of bacteremia No 532/578 (92.0) 521/564 (92.4) -0.3 (-3.5, 2.8) Yes 22/26 (84.6) 21/21 (100) -15.4 (-33.8, 1.5) Previous systemic antibacterial usage Yes 356/377 (94.4) 353/374 (94.4) 0.0 (-3.4, 3.4) No 203/233 (87.1) 196/218 (89.9) -2.8 (-8.8, 3.2) Infection Type Cellultis 213/229 (93.0) 222/243 (91.4) 1.7 (-3.4, 6.7) Abscess 187/205 (91.2) 179/190 (94.2) -3.0 (-8.4, 2.3) Infected Wound 73/84 (86.9) 65/73 (89.0) -2.2 (-12.8, 8.7) Infected ulcer 48/53 (90.6) 47/50 (94.0) -3.5 (-15.7, 8.3) Infected burn 25/25 (100) 18/18 (100) 0 (-13.6, 17.9) Clinical Outcomes: Efficacy of ceftaroline was similar to vancomycin+aztreonam in the CE and MITT populations. Similar cure rates for patients with diabetes or peripheral vascular disease Clinical cure rates in CE population for MRSA bacteremia: 85.7% ceftaroline vs. 100% vancomycin+aztreonam; [95% CI -14.3 (-53.5 to 58.4)]. However, more patients in the ceftaroline group had staphylococcal bacteremia (18 vs. 9). Clinical Failure/Relapse: 4/26 patients in the ceftaroline group were classified as having experienced clinical failure (secondary to adverse events, co-infection with resistant pathogen and surgical intervention) Clinical relapse at the late follow-up visit was noted in 1.1% ceftaroline group vs. 0.9% of patients in the vancomycin + aztreonam group Microbiological Efficacy: Favorable microbiological responses (ME population) observed in 92.3% ceftaroline vs. 93.7% vancomycin + aztreonam (-1.4%; 95% CI, -4.8% to 2.0%) Patients with > 1 gram positive pathogen had similar microbiological responses observed in 93.5% ceftaroline vs. 93.8% vancomycin + aztreonam (-0.3%; 95% CI, -3.7% to 3.1%) Patients with > 1 potential gram-negative pathogen, favorable per-pathogen microbiological response achieved in 86.3% ceftaroline vs. 93.6% vancomycin + aztreonam (-7.4%; 95% CI, -16.6% to 1.3%)ConclusionsCeftaroline monotherapy is efficacious for the treatment of cSSSI, with a clinical cure rate comparable to that of vancomycin and aztreonam. Efficacy of ceftaroline monotherapy was consistent in the various study population (ie, CE, MITT, ME, and mMITT). Similar clinical cure rates between patients infected with single or multiple pathogens, across infection types (including cellulitis, major abscess, and infected wound), and between patients with common comorbidities, such as diabetes mellitus and peripheral vascular disease. CANVAS 1 and 2 studies serve to provide efficacy data in the context of the current endemicity of MRSA, a crucial cSSSI pathogen Vancomycin and aztreonam demonstrated higher favorable microbiological response compared to ceftaroline monotherapy against Gram-negative infectionCritiqueStudy Strengths: Phase 3, large, randomized, international, double-blind comparative study Baseline characteristics were comparable between both groups Study Limitations: Limited data on efficacy in special populations (ie, patients with CrCL <30ml/min or receiving hemodialysis were excluded from the study). No consistency in dosage adjustments for vancomycin as this was a multicenter, international study with different clinical practices at different sites; unknown if patients were appropriately dosed based on actual body weight and renal function Appendix B: Summary of Phase III Community-Acquired Bacterial Pneumonia (CABP) Clinical Trials8 CitationFile T et al. Integrated Analysis of FOCUS 1 and FOCUS 2: Randomized, Double-Blinded, Multicenter Phase 3 Trials of the Effiicacy and Safety of Ceftaroline Fosamil vs. Ceftriaxone in Patients with Community-Acquired Pneumonia. Clinical Infectious Diseases 2010;51(12):1395-1405Study GoalsEvaluate the efficacy and safety of ceftaroline compared with ceftriaxone for treatment of CABP MethodsStudy Design FOCUS 1 and FOCUS 2: Ceftaroline community acquired pneumonia trial vs ceftriaxone in hospitalized patients Two similar, phase III, multinational, multicenter, randomized, double-blind, comparative efficacy and safety clinical trials Compared the efficacy and safety of ceftaroline versus ceftriaxone administered for 5-7 days to adults hospitalized (non-intensive care unit admit) with community acquired pneumonia with Pneumonia Outcomes Research Team (PORT) risk class III or IV Randomization was stratified by PORT risk class Study Groups: Ceftaroline 600 mg IV every 12 hours Ceftriaxone 1 g IV every 24 hours Ceftaroline dose was renally adjusted to 400 mg in patients with moderate renal impairment (CrCl 31- 50 ml/min) Difference between FOCUS 1 and Focus 2 trial: In Focus 1 trials, patients received 2 doses of oral clarithromycin 500mg adjunctive therapy to enable enrollment from North America. However, macrolide treatment limited to a 24-hour course. Study Populations: Intent to treat (ITT) Modified intent-to-treat (MITT) MITT Efficacy (MITTE) Microbiological MITT Efficacy (mMITTE) Clinically evaluable (CE) Microbiologically evaluable (ME) Efficacy/Outcome Measures: Primary outcome: Per-patient clinical cure rate at the test-of-cure visit (8-15 days after last dose) in CE and MITTE populations Secondary outcomes: Clinical cure in the microbiologically evaluable (ME) and microbiological MITTE (mMITTE) populations at TOC Clinical cure at the end-of-therapy (EOT) visit Microbiological outcome at TOC Overall (clinical and radiographic) success at TOC Clinical and microbiological response by pathogen at TOC Clinical relapse at the late follow-up 2135 days after last dose) visit Microbiological reinfection or recurrence at late follow-up Safety (incidence of AEs and SAEs) Laboratory assessments: Multidrug-resistant Streptococcus pneumonia (MDRSP) were defined as strains resistant to > 2 antimicrobial classes (Penicillin, macrolide, tetracycline, fluoroquinolones, chloramphenicol, trimethoprim-sulfamethoxazole, and cephalosporins) Patients with infections caused by Legionella pneumophilia, Mycoplasma pneumonia, Chlamydophilia pneumonia were excluded from CE, mMITTE and ME populations Data Analysis: Point estimate for clinical cure rate of 90% in the CE population in both treatment groups. Sample size of 618 patients were required for each study for > 90% power. Non-inferiority margin set at 10%; nonevaluable rate of 25%.CriteriaInclusion Criteria: Adults > 18 years of age Radiographically confirmed CAP requiring hospitalization and treatment with IV antimicrobial therapy PORT score 71 to < 130 (PORT risk class III or IV only) Acute illness (< 7 days duration) with > 3 clinical signs or symptoms of lower respiratory tract infection: new or increased cough, purulent sputum or change in sputum character, auscultatory findings consistent with pneumonia , dyspnea, tachypnea, or hypoxemia, temperature > 38oC or hypothermia, WBC > 10,000 cells/mm3 or < 4500 cells/mm3, > 15% immature neutrophils (bands) irrespective of WBC count Exclusion Criteria: PORT risk class I, II, or V Admission to an ICU at baseline CAP suitable for outpatient therapy with an oral antimicrobial agent Confirmed/suspected respiratory tract infection attributed to hospital-acquired or health care-associated pathogens Noninfectious cause of pulmonary infiltrates or pleural empyema Infection with a pathogen resistant to study medication Epidemiologic or clinical likelihood of resistant pathogens including ceftriaxone-resistant organisms Risk factors for MRSA infection or predominance of gram-positive cocci in clusters on sputum Gram stain Known or suspected infection caused solely by an atypical pathogen (Chlamydophila pneumoniae, Mycoplasma pneumoniae, and Legionella species) at baseline Positive Legionella urinary antigen test result at baseline Previous therapy with an antimicrobial for treatment of CAP within 96 hours prior to randomization Receipt of chronic concomitant systemic corticosteroids > 40 mg of prednisone equivalent Severe renal impairment (CrCl < 30 mL/min) Significant hepatic disease: Acute viral hepatitis, AST or ALT > 10-fold the ULN or total bilirubin > 3-fold the ULN, or manifestations of end-stage liver disease, such as ascites or hepatic encephalopathy Hematologic disease: Neutropenia defined as < 500 neutrophils/mm3 or thrombocytopenia defined as platelet count < 60,000 platelets/mm3 Immunologic disease: HIV with CD4+ cell count < 200 cells/mm3 or current diagnosis of an AIDS-defining illnessResultsEnrollment 1240 total patients randomized (614 patients each arm) MITTE populations evaluated: FOCUS 1: 591 patients (July 2007-June 2009) FOCUS 2: 562 patients (January 2008-June 2009) Baseline demographics Mean (+ SD) duration of study drug treatment was: CE population: 6.6 + 0.9 days MITTE population: 6.5 + 1.1 days Overall, 88% patients (293/333) had CAP caused by a typical pathogen only No patient had a positive Legionella antigen test 12% (40/333) had CAP due to a mixed infection (typical and atypical pathogens) Most common pathogens included S. pneumonia (41.7%; 139/333) and S. aureus (16.5%; 55/333) Baseline Characteristic Ceftaroline (n = 580) Ceftriaxone (n = 573) Age (Mean years + SD) 60 + 16.4 61.6 + 15.6 Common comorbid conditions, no.(%): Structural lung disease Any prior pneumonia Asthma 160 (27.6) 123 (21.2) 49 (8.4) 147 (25.7) 92 (16.1) 38 (6.6) PORT risk class, no.(%) III IV 360 (62.1) 220 (37.9) 353 (61.6) 220 (38.4) Bacteremia, no. (%) 23 (4.0) 20 (3.5) Renal impairment, CrCl (mL/min); no.(%) Mild (51-80) Moderate (31-50) 199 (34.3) 88 (15.2) 190 (33.2) 85 (14.8) Clinical Outcomes Clinical Cure Rates by Study Population at the Test-of-Cure Visit Integrated FOCUS CE (co-primary efficacy) MITTE (co-primary efficacy) ME mMITTE Ceftaroline, no. (%) 387/459 (84.3) 479/580 (82.6) 131/154 (85.1) 138/165 (83.6) Ceftriaxone, no. (%) 349/449 (77.7) 439/573 (76.6) 111/147 (75.5) 126/168 (75.0) Weighted treatment difference, % (95% CI) 6.7 (1.6-11.8) 6.0 (1.4-10.7) 9.7 (0.7-18.8) 8.7 (-0.0-17.4) Clinical Cure Rates by Common Baseline Pathogens at Test-of-Cure Visit in Microbiological Modified Intent-to-Treat Efficacy (mMITTE) Population Microbiological Pathogen Ceftaroline group no. (%) Ceftriaxone group no. (%) Streptococcus pneumoniae MDRSP 59/69 (85.5) 4/4 (100) 48/70 (68.6) 2/9 (22.2) S. aureus (MSSA) S. aureus (MRSA) 18/25 (72) Not Applicable 18/30 (60) 1/2 (50) Haemophilus influenzae 17/20 (85) 20/24 (83.3) Haemophilus parainfluenzae 16/17 (94.1) 15/18 (83.3) Klebsiella pneumoniae 14/15 (93.3) 10/13 (76.9) Escherichia coli 10/12 (83.3) 9/13 (69.2) Clinical Cure Rates in Select Patient Subgroups in Clinically Evaluable Population, no. (%) Subgroup Ceftaroline Ceftriaxone 95% CI Bacteremia 15/21 (71.4) 10/17 (58.8) 12.6 (-17.6 to 41.6) PORT risk III 249/287 (86.8) 217/274 (79.2) 7.5 (1.3-13.8) PORT risk IV 138/172 (80.2) 132/175 (75.4) 4.7 (-4.1 to 13.5) Prior antibiotic treatment 152/185 (82.2) 158/194 (81.4) 0.7 (-7.2 to 8.6) No prior exposure to antibiotics 235/274 (85.8) 191/255 (74.9) 11.2 (4.5-18.0) Aged >50 years 304/362 (84.0) 278/351 (79.2) 4.8 (-0.9 to 10.6) Aged >65 years 195/232 (84.1) 177/219 (80.8) 3.4 (-3.7 to 10.5) Aged >75 years 90/111 (81.1) 83/105 (79.0) 3.3 (-7.4 to 14.1) Mild renal impairment (51-80 mL/min) 133/164 (81.1) 115/151 (76.2) 5.3 (-3.8 to 14.4) Moderate renal impairment (31-50 mL/min) 62/75 (82.7) 50/63 (79.4) 3.5 (-9.7 to 17.2) Microbiological Outcomes: Favorable per-patient microbiological response rates in ME population: Ceftaroline: 87% (134/154 patients) and Ceftriaxone: 81% (119/147 patients); [6.1%; 95% CI, -2.3% to 14.6%] Results consistent in the mMITTE population No patient met the criteria for microbiological reinfection or recurrence at late follow-upConclusionCeftaroline 600mg administered every 12 hours for 5-7 days to hospitalized patients with CAP (PORT risk III or IV) is an efficacious, well-tolerated treatment, comparable to ceftriaxone Ceftaroline is efficacious against CAP caused by S. pneumonia and subset of patients with S. pneumonia bacteremiaCritiqueStrengths: Phase 3, large, randomized, international, double-blind compar (@`gijkD M   9 : R whd`d\XThqNh!hxh}hw3h h 5>*H*OJQJh OJQJhAh~SOJQJ#hrIh*p6B*CJ]aJph#hrIh3C<6B*CJ]aJph#hrIh#6B*CJ]aJph#hrIh&{6B*CJ]aJph h#CJ h&`CJ h~SCJh~ShPhPCJ^J hnMCJ hPCJ(@ : 4 rS~qi & F gd & F7$8$H$gd & F7$8$H$gd  & Fgd gdgdrI"(($d&d-DM NPgd~q$d&d-DM NPgd~q$d&d-DM NPgd~q R a     > ?    ' / 0 3 4 9 M c g m Ȼܷܻܫܧܧܻܧܑ h*zYh h*zYh*zY h*zYh4 h*zYh+h)oQh*zY6h*zYhzh)oQh)oQ6hx h)oQ6h)oQhie6h)oQhx6h*uhieh}h)oQh4hqNh)oQh!6h)oQhqN6h!h+2 :@nqr-3RSdfмۑzssofobh!h5zhaJh5z h Wh Wh Wh WaJ h`4h`4 h)oQhZi h)oQhz h*zYh*h*zY h*zYh+ h*zYh4h)oQh*zYOJQJh)oQOJQJh`4h)oQ6OJQJh`4h)oQOJQJh)oQhzh)oQOJQJhzh]OJQJhzh*zYOJQJ$f   no'G?avǸ}n_h:@hN<CJOJQJaJh:@hCJOJQJaJh2CCJOJQJaJ h2Ch2Chbeh!h4hAh*hCLhvh hH*OJQJh h 5>*H*OJQJhOJQJ hAh= hAh hAh~ShAh~SOJQJhh Wh5zaJhN#S  no $$Ifa$gd% $Ifgd|Z$gd2CgdN<gd2Cgd & F gd   ",8:<>PZ\fhrt¾º²ˁzu hbe\ hbe>*\h%h|Z\ hbeh%hbeh%5 hbeh*hbeh*5hbe hbehbehbehbe5h%h*h| hbe5h%h|5h:@h|CJOJQJaJh:@hbeCJOJQJaJh:@hACJOJQJaJ,vm $Ifgd% $Ifgd|kd$$Ifl0%t t0644 layt)oQvm $Ifgd% $Ifgd|kd$$Ifl0%t t0644 layt)oQvm $Ifgd% $Ifgd|kd8$$Ifl0%t t0644 layt)oQvm $Ifgd% $Ifgd|kd$$Ifl0%t t0644 layt)oQ"<vm $Ifgdbe $Ifgd|kdp$$Ifl0%t t0644 layt)oQ<>\vvm $Ifgd% $Ifgd|kd $$Ifl0%t t0644 layt)oQtvx 23Zdfhl02l -|x|pkpcp_h]h]h4^6 h4^6hAh4^6hiehYt hYt\hfCJOJQJ^JaJh6\h6\\ h6\aJhfhfaJ hfaJhf hf\huFhrh4^h)oQ hr\ hND\ hH*\hND5>*\ h {5\h|Zh%h|5h| h|Zh|%vxvm $Ifgd% $Ifgd|kd$$Ifl0%t t0644 layt)oQ J!K! "!""""}xxxxxx}}}o $Ifgdsgd4^kdD$$Ifl 0%t t0644 layt)oQ -DElnqz#,?HRYz  ! ¾­•{t hYrh +UhYrh[h +U6h*zY h6 hl6h +UhuFhh]hfhl\h4^h4^6 h4^6h)oQh4^hl huFhl huFh4^huFh4^6huFhl6 huFh:i huFhuF huF6huFh:i6-! X I!J!~!!!!!!!!!!" " """ "!"+"."7"9"X""""""""yh hnhnB*CJ\aJph hN<H*\ hpgH*\ hpg5\h:@h'5\h:@hND5H*\h:@hND5\h:@h5\h:@hqN5\hNDB*\phhvthvt6 h +Uh +Uhz hz6 h +U6hvthh\h[hh +U$"""""#V#X#a#b#c##########L$M$N$]$^$_$u$$$$$$$$$$$$%C%D%E%O%P%Q%b%n%y%%%%%%%%%%%%%&&ŻŻ㻴ŻŻŻŻŻŻŻŬŬŬͬŬ hn5\h<9hn5\h`Thn\ hpg5\h<9hpg5\h`Thpg\h`Thpg56\h`Thpg5H*\hq hpg5\#hnhpg6B*CJ\aJph="""#4#W#X#]#b#ul__ $If^gdpg $Ifgds}kd$$Ifl04,"  t0644 layts $$Ifa$gdsb#c#######xkk___ $$Ifa$gds $If^gdpg $Ifgds}kd$$Ifl04,"  t0644 layts###$!$M$N$T$Y$^$xkkk____ $$Ifa$gds $If^gdpg $Ifgds}kd,$$Ifl04,"  t0644 layts ^$_$u$$$$$$xkk___ $$Ifa$gds $If^gdpg $Ifgds}kd$$Ifl04,"  t0644 layts$$$$$$xk__ $$Ifa$gds $If^gdpg $Ifgds}kdx$$Ifl04,"  t0644 layts$$%$%D%E%K%P%xkk___ $$Ifa$gds $If^gdpg $Ifgds}kd$$Ifl04,"  t0644 laytsP%Q%b%%%%%%xkk___ $$Ifa$gds $If^gdn $Ifgds}kd$$Ifl04,"  t0644 layts%%%%& &&&vii]]] $$Ifa$gds $If^gdpg $Ifgdskdj $$Ifl04,"  t0644 laytn&& &&&&&B&E&F&Q&U&&&&&'''#'&'6'?'N'Z']'a'h'''''ɺ~uoeu[uTeTeuTeuTeu h +U6aJhIh'5aJh'h'6aJ h +UaJh'h'aJh'h'\aJh^hNCJaJh^h^B*CJaJphh%B*CJaJphhB*CJaJphhh~S5>*H*OJQJh5>*H*OJQJhAh~SOJQJhfh`Thpg\h<9hpg5\hq hpg5\&&&F&&j'H(I(,|sk__ZUgdAgdN & Fgd 'dgd^gdgdR}kd $$Ifl04,"  t0644 layts''(((((( (,(.(9(?(F(H(I(((t)u)v)))))ҮhWGhAB*CJOJQJaJph hAhA0JCJOJQJaJ4j hAhAB*CJOJQJUaJph.jhAhAB*CJOJQJUaJph%hAhAB*CJOJQJaJph%h^h'B*CJOJQJaJphh'h'6aJ h +U6aJh'h'aJhIh'5aJhIh'aJhIh'6aJ hI6aJ)^******+H+L+a+b+++++++++,,,,H,L,M,_,񲣔xmaRIhCih|Z0J,h h~S5>*H*OJQJh 5>*H*OJQJhWh~SOJQJhhU$CJ%hAhB*CJOJQJaJphh2ChA`.CJOJQJaJh2ChD:<CJOJQJaJhD:<CJOJQJaJh/#vCJOJQJaJh'nCJOJQJaJh WCJOJQJaJhAhOCJOJQJaJhAhU$CJOJQJaJ,,M,A-B-../.m/n///080 $Ifgd:Agd3 gd:AgdNgd|Zgdh^hgdU$ _,,,,,,,,,,,,,,,,, --#-%-.-0-4-?-@-A-B-V-i-k-v-x------------. ...+.hWh~SOJQJ h0I0J, h?aJ hLaJ h*uaJhLh:AaJhLhLaJhLhCiaJhLh|ZaJ hCih|ZhLh0IhCih|Z h|Z0J, h|Z0J,5hCih|Z0J,hCih%0J,0+.../.1.O.b.o.u.y....l/m/n/////////////0(080=0[0]0^0_0a0ٴɩrerZh3 h3 B*phhWh3 B*\phhWh:AB*\phh:@h:A5B*\phh:@hqN5B*\phh:@h3 5B*\phh2ChrIB*phh:Ah:A5B*phhBB*phh3 B*phh$IB*phh:Ah:AB*phhh~S5>*H*OJQJh5>*H*OJQJ#8090=0\0{r $Ifgd3 $Ifgd:Azkd1 $$Ifl0,"0644 layt:A\0]0i00{{ $Ifgd3 zkd $$Ifl0,"0644 layt:Aa0b0c0d0e0f0i0r0000000000000000&1(1)11111112 2 2222233콰ץ젘}y}r}k hh hhhzhh5>*H*OJQJhWh~SOJQJh+b-B*ph hN>*h$Ih$IB*phh$Ih$IB*CJphh$Ih$IB*H*phh3 h:A>*B*phhBB*phh3 h3 >*B*phh:Ah:AB*phh3 B*ph(0000{r $IfgdB $Ifgd3 zkdU $$Ifl0,"0644 layt:A000'1{{ $Ifgd:Azkd $$Ifl0,"0644 layt:A'1(11111 2@4A4]4n4}tojjb & Fgd gdgd'ngdgd3 zkdy$$Ifl0,"0644 layt:A 333?4@4A4\4]4m4n44444444444444444555555!5οyl__Sh6\CJOJQJaJhc/5CJOJQJaJh'n5CJOJQJaJh6h6\CJOJQJaJhc/CJOJQJaJh'nCJOJQJaJhc/hc/CJOJQJaJ hc/hc/hc/hc/aJhc/hc/5B*aJphh'n5B*aJphhc/B*aJphhB*aJphh hh hh n4445555~6666666667 $$Ifa$gdS $Ifgd6\gd6\ & Fgd  & Fgd gdc/ & Fgd !5<5F5P5Q5Y5_5g5h5n5o5q5r5w5x555566Q6}6666667 777777P7Q77ʹyp`\ypph{hS h{5CJOJQJaJhS h6aJhS h65CJOJQJaJhS h6CJOJQJaJh{CJOJQJaJh6h{5CJOJQJaJh/5CJOJQJaJhjCJOJQJaJh6\CJOJQJaJhc/CJOJQJaJhc/hc/CJOJQJaJh'nCJOJQJaJ$7 77777^UUUU $Ifgd6\kd $$Ifl\Y \<' e K  t0644 laytS 777/7?7P7^UIII $$Ifa$gdS $Ifgd6\kd$$Ifl\Y \<' e K  t0644 laytS P7Q7V7f7v77^UIII $$Ifa$gdS $Ifgd6\kd$$Ifl\Y \<' e K  t0644 laytS 777777^UUUU $Ifgd6\kdH$$Ifl\Y \<' e K  t0644 laytS 77777777788888;8<8=88888888899999H9I99˼zkbRkbkbkbkbkbkhS h{5CJOJQJaJhS h{aJhS h{CJOJQJaJh{CJOJQJaJh6h{5CJOJQJaJh{5CJOJQJaJh/5CJOJQJaJh6CJOJQJaJhS h6CJOJQJaJhS h65CJOJQJaJhS h{5CJaJhS h{5CJOJQJaJhS h6aJ 777777^UIII $$Ifa$gdS $Ifgd6\kd$$Ifl\Y \<' e K  t0644 laytS 777778^UIII $$Ifa$gdS $Ifgd6\kd$$Ifl\Y \<' e K  t0644 laytS 888<8=8J8O8[8^YYPDDD $$Ifa$gdS $Ifgd{gd6\kd$$Ifl\Y \<' e K  t0644 laytS [8`8u8888888RIIII $Ifgd{kdD$$Ifl\ <<' e K  t0644 laytS $$Ifa$gdS 888888^UIII $$Ifa$gdS $Ifgd{kd$$Ifl\ <<' e K  t0644 laytS 888889^UIII $$Ifa$gdS $Ifgd{kd$$Ifl\ <<' e K  t0644 laytS 999999^UUUU $Ifgd{kd$$Ifl\ <<' e K  t0644 laytS 999'979H9^UIII $$Ifa$gdS $Ifgd{kd@$$Ifl\ <<' e K  t0644 laytS H9I9N9^9n99^UIII $$Ifa$gdS $Ifgd{kd$$Ifl\ <<' e K  t0644 laytS 9999:<^YRE8 & F 7$8$H$gd & F 7$8$H$gd gdgdkd$$Ifl\ <<' e K  t0644 laytS 9999999I:q:::::::;;<<</<0<<<<<====6=9=ٵ{{ri^Rh5>*H*OJQJhWh~SOJQJhkhaJhh WaJhhk6aJ hzaJhhkaJhh WOJQJhhQ9OJQJhh8 OJQJhhkOJQJ hh W hh8 h*u hhk hhQ9 hhhCJOJQJaJhzhS h{aJ<==:=>>??"@0@F@\@ &$$Ifa$gdnk# &$Ifgdcm'dgdqNgdG-]'dgdG-]gdh^hgd & F gd 9=:===>>>>>>????????@!@"@ɺn]K]: h:@hcm5B*CJaJph#h:@h5>*B*CJaJph h:@hG-]5B*CJaJph#h:@hcm5B*CJH*aJph h:@h5B*CJaJphh/5B*CJaJphhz^B*CJaJphhhG-]B*CJaJphhhG-]CJOJQJaJhG-]B*CJaJphhcmB*CJaJphhG-]hG-]B*CJaJphhh~S5>*H*OJQJ"@/@\@]@l@m@z@{@@@@@@@@@@@@@A(AXA\AuAAAAAA]BiBrBBBBCC7CFC\CcCuCvCCÿÑzzzphvB*aJphh_esB*aJphhz^h_esB*aJphh_es hz^hz^ hz^6h:ihvB*phhvhcmh:i h:ihz^hz^h}vIhG-]CJOJQJaJ hCJhjhCJaJhhjh5CJaJhjh=5CJaJ,\@]@f@i@l@qh\\ &$$Ifa$gdnk# &$Ifgdcmkd}$$IflF ,"   t06    44 laytnk#l@m@t@w@z@qh\\ &$$Ifa$gdnk# &$Ifgdcmkd $$IflF ,"   t06    44 laytnk#z@{@@@@qh\\ &$$Ifa$gdnk# &$Ifgdcmkd$$IflF ,"   t06    44 laytnk#@@@@@qh\\ &$$Ifa$gdnk# &$Ifgdcmkd$$$IflF ,"   t06    44 laytnk#@@@@@qh\\ &$$Ifa$gdnk# &$Ifgdcmkd$$IflF ,"   t06    44 laytnk#@@@@@qh\\ &$$Ifa$gdnk# &$Ifgdcmkd>$$IflF ,"   t06    44 laytnk#@@@@@qh\\ &$$Ifa$gdnk# &$Ifgdcmkd$$IflF ,"   t06    44 laytnk#@@@@@qh\\ &$$Ifa$gdnk# &$IfgdcmkdX$$IflF ,"   t06    44 laytnk#@@A(ABC*\he he 5CJOJQJaJ(h:ihcm5B*CJOJQJaJph(h:ihe 5B*CJOJQJaJph(he he 5B*CJOJQJaJphh}vIhe CJOJQJaJh}vIh~SCJOJQJaJh_esCJOJQJaJhz^haJ h_esaJhhmaJ hmaJhvB*aJphhz^h_esB*aJphh_esB*aJphFFF]G^G_GtGHFILMMNKNLNNOOOOO$IfgdKgd}vI&gd1ZS' & Fgd ' & Fdgd & & Fdgd & & Fdgd &dgd FFFFFFF#G8G^G_GsGtGGGGGGG3HHHHٻ{maXaMBhQhCLCJaJhQhe CJaJhQCJ\aJhQhCJ\aJhQhCL5CJ\aJhQhCLCJ\aJhQhe CJ\aJh}vIhe CJ\aJhh 5>*CJaJh h 5>*CJaJh2C5>*CJaJhCLCJaJh he CJaJh CJaJhh 5>*CJ\aJh he 5>*CJ\aJHHHHHHHHHHHHH2I4IEIFIgIhIiIkIIIź~rfXJ?h8 he CJaJh8 h5CJ\aJh8 h[f5CJ\aJh8 h[fCJ\aJh8 he CJ\aJhh[fCJaJhCLCJaJh CJaJh8 CJaJh he CJaJh he 5CJ\aJh 5CJ\aJh}vIh CJ\aJh8 CJ\aJh}vIhe CJ\aJh}vIhe 6CJ\]aJhhCLCJaJII.JJJJK4KmKKKKKKKLELLLLLLM/M0M2MIMMMMMMMNNN Nǻꢚꏊ~ri^h9h1ZSCJaJhv5CJaJh9h1ZS5CJaJh9hQ5CJaJ h}vI5h8 h1ZSCJaJh8 CJaJh8 hS KCJaJh8 h[f5CJ\aJh8 h[fCJ\aJh8 he CJ\aJh8 hS KCJ\aJh8 hCJaJh8 he CJaJh8 h[fCJaJ$ NNNNJNKNLNNOOOOOOOOOOOOOPP PPPP%P&P'P+P,P-P1PžxhdZVdhcmhOJPJQJhhB*OJPJQJaJphhKhB*H*ph!hcmhcmB* OJPJQJphI}hcmB* OJPJQJphI}hB*phhCJOJPJQJ hCJ hKhKhK hUhKh}vIh~SOJQJ h8 5hv5CJaJh9hQ5CJaJh9hQCJaJ!OOOP$IfP Pkdr$$Ifֈ1A&d,  t<522 l4ap<yt PPP'P,P-P2P7P8P=PBPCPHPMPNPSP_P`PeP d$If$If d$If $Ifgdcm1P2P6P7P8Pkd $$Ifl\x4,"   04 laytE\ $$$Ifa$gdA $$$Ifa$gdE\gdMdgd}vIQQQQQQ=RTI $$IfgdCikd!$$Ifl\x4,"   04 laytE\ $$$Ifa$gdE\QQQQQQQ=R>RHRIRKR[RbRcRhRiRnRoRpR{R|RRRRRRRRRRRRRRξ}}rccWch8 CJOJQJaJhCih%SCJOJQJaJhh/CJaJ h/h/CJOJPJQJaJh/h/CJOJQJaJhCih/CJOJQJaJ hAH*aJhhCiCJaJh/hCi5CJOJQJaJhhMdCJaJhACJOJQJaJhCihMdCJOJQJaJh/CJOJQJaJ"=R>RKRbRhRoR $$$Ifa$gd%Sckd"$$Ifl,""04 layt' oRpR|RRRRRRbVVHHHH $$$Ifa$gd/ $$Ifa$gd/kd#$$Ifl1\x4,"   04 layt%SRRRRRSdXXXX $$Ifa$gd' kd#$$Ifl\x4,"   04 laytE\RRRRRSSS SS"S#S*S+S1S2S3S?SSSZSaShSiSoSpSvSwSxSSSSSSSֳֿֿ֦֍ֳֿ}n_nh/hxCJOJQJaJh/h8 CJOJQJaJh/h%S5CJOJQJaJh%SCJOJQJaJhACJOJQJ\aJh/CJOJQJ\aJhACJOJQJaJhh%SCJaJh9CJOJQJaJhCih%SCJOJQJaJh:ih%SCJOJQJaJh/CJOJQJaJ!SS S"S*S2SdXXXX $$Ifa$gdE\kd$$$Ifl\x4,"   04 laytE\2S3S?ShSoSwSdXXXL $$Ifa$gdA $$Ifa$gd' kd_%$$Ifl\x4,"   04 laytE\wSxSSd[ $Ifgd%Skd#&$$Ifl\x4,"   04 laytE\SSSSSS $$Ifa$gd' akd&$$Ifl,""04 layt' SSSSSSTTTTTTT)T9T@TATFTGTLTMT[TkTrTwTxT~TTT˼ڭxixZZOhh%SCJaJhCih%SCJOJQJaJh/hACJOJQJaJh/h%SCJOJQJaJhhw(CJaJhw(hw(CJOJQJaJhw(CJOJQJaJhCihw(CJOJQJaJh/h9CJOJQJaJh/h8 CJOJQJaJhh8 CJaJh/CJOJQJaJhCih8 CJOJQJaJSSSTTTdXXXX $$Ifa$gd' kdi'$$Ifl\x4,"   04 laytE\TT)T@TFTLTdXXXX $$Ifa$gdw(kd-($$Ifl\x4,"   04 laytE\LTMT[TrTxTTd[OOO $$Ifa$gd' $Ifgd' kd($$Ifl\x4,"   04 laytE\TT)U*UDUUUUXd_ZQLLQGgd*gdCLgdqNgdMdgdMdkd)$$Ifl\x4,"   04 laytE\TTTTTTTTT UU$U(U)U*UDU^UoUUUUUoVpVVVVWWWWDX^XbXpXqXXߝzvrvnvnvrnrjrfnrh:+hvh*h h hCLhqNaJ hCLaJhCLhCLaJh}vIh~SOJQJ%hhMdB*CJOJQJaJphhAhACJ\ hCJ\ hACJ hACJ\ hxCJ\hAhMdCJ\hAhMdCJhAhACJ hxCJH* hACJH*$XXXXXXXXXXXXXXXXXYY@YAYYL[h[{[[[ \(\;\<\U\~qaqaqPq!h hvt0J-B*OJQJphh hvt0J-6OJQJ]h hvt0J-OJQJhvth0J-6CJ]hvth0J-CJh~SB*OJQJphhvth[fB*OJQJphhB*H*OJQJphhB*OJQJphh}vIh~SOJQJh*h h8 h:+aJh?&h:+6aJh:+h h 6XXXAYYZ{[<\\6^_`=aaab $Ifgd $Ifgdgdc  & F7$8$H$gd  & Fgd  & Fgd gdqNgd*U\\\\\^"^5^6^h____``}`~```````aa$aa_aeafagaaa˴ˡzzkh5CJH*OJQJaJh_OCJOJQJaJh_Oh6CJOJQJaJh[CJOJQJaJh OJQJh h OJQJh h0IOJQJh hvt6OJQJh h B*OJQJphh hvtOJQJ\h hvt6OJQJ\]h hvtOJQJ"aaaaabbbbbbccc(c+cDcccccϰϛ|j|j|j|UFh_OhL5B*aJph(h_OhL5B*CJOJQJaJph"h} 5B*CJOJQJaJph"hz#A5B*CJOJQJaJphh_OhLB*aJph(h} hL5B*CJOJQJaJph"h} h} 56CJOJQJaJh5CJOJQJaJh} h} 5CJOJQJaJh_OhLCJOJQJaJ"hhL5CJH*OJQJaJbbbct $Ifgdz#A $Ifgdvkdy*$$Ifl 0("0(4 lalyt ccccdddd2e3eftkkk^^kk  & F$Ifgd $Ifgd?& $Ifgd?& $Ifgdvkd+$$Ifl0("0(4 lalyt ccccccccccccccccccKdkdzd|d~ddddddddԷԫԞpdXdXhVCJOJQJaJhz#ACJOJQJaJ"h8h856CJOJQJaJhcmhz#ACJOJQJaJhz#A5CJOJQJaJh?&5CJOJQJaJhcmCJOJQJaJhcm5CJOJQJaJhPhP>*CJOJQJaJhPCJOJQJaJhGhPCJOJQJaJhWQhL>*CJOJQJaJddd2e3eeeeefffffffff ggggg{l\M;"hWQhWQ5>*CJOJQJaJhWQ5>*CJOJQJaJhWQhG5CJOJQJaJhGhWQCJOJQJaJhWQCJOJQJaJhWQh8CJOJQJaJhWQ56CJOJQJaJhz#Ahz#ACJOJQJaJhGCJOJQJaJh?&CJOJQJaJh8h8>*CJOJQJaJhz#ACJOJQJaJhVCJOJQJaJh8CJOJQJaJffHfffffgEg_ggggg+h?hdhhi%i $Ifgd  & F$Ifgd $IfgdWQ h$If^hgdG h$If^hgdz#A  & F$Ifgd $Ifgd?&gggggh+h>h?hhii#i$i%iriiijjj!jĸĸĩĩueVGhhLCJOJQJaJh_OhL5B*aJphhGhL5CJOJQJaJhGhWQCJOJQJaJhG5CJOJQJaJhGCJOJQJaJhWQCJOJQJaJh?&hLCJOJQJaJhz#ACJOJQJaJh?&hWQCJOJQJaJhWQhWQ5CJOJQJaJhWQ56CJOJQJaJhWQ5CJOJQJaJ%ijj!j5jDjjkklRm{rreeeeXX  & F$Ifgd  & F$Ifgd $Ifgdvkd+$$Ifl,0("0(4 lalyt  & F$Ifgd !j3j4j5j9j:jjjjjjjkkkkkkMlNlllllllllllĵߵyj[jyjKyh@hCJH*OJQJaJh@hhWCJOJQJaJh@hCJOJQJaJh@h>*CJOJQJaJh@>*CJOJQJaJh?&hhWCJOJQJaJh?&h>*CJOJQJaJh?&hCJOJQJaJhGh?&CJOJQJaJhCJOJQJaJhh>*CJOJQJaJhhL>*CJOJQJaJlQmRmdmemfmqmmmnncndnnnpppppp(qѵ}n_OC7hX3CJOJQJaJh*CJOJQJaJh`8h`85CJOJQJaJhhLCJOJQJaJh_OhL5B*aJphh?&hhW6CJOJQJaJhLCJOJQJaJhhWhhW>*CJOJQJaJhhWCJOJQJaJhhWhhWCJOJQJaJhhW>*CJOJQJaJhhWhL>*CJOJQJaJh?&h>*CJOJQJaJh?&hhWCJOJQJaJRmfmn^nonnoop4pVpppprvkd\,$$Ifl0("0(4 lalyt  & F$Ifgd $Ifgd ppplqmq{qqr8rrrrrrss $$Ifa$gd7 ' $$Ifa$gd7 'K$ $Ifgd`8 & F$Ifgd & F$Ifgd h$If^hgd`8  & F$Ifgd $Ifgd`8 $Ifgd(q)q-q?qhqlqmq{qqqqqqq r rrr7r8rDrrrpcTJc@hnMB*aJphh@<B*aJphhnMhnM6B*aJphhnMhnMB*aJphhGhnM6B*aJphhGhnM>*B*aJphhGhnMB*aJphh*hGCJOJQJaJ hG6aJh*hnMCJOJQJaJh`8h`85CJOJQJaJh`8CJOJQJaJhX3CJOJQJaJhz#ACJOJQJaJh*CJOJQJaJrrrrrrrrss(s)s5s6sBsCsDsWsXshsisyszs{ssssssss̽wwjjjj]jNjjh7 'h@<>*B*aJphh7 'h&cB*aJphh7 'h@<B*aJphh7 'hnMB*aJphh7 'hnLB*aJphh7 'hBFB*aJphh7 'hT%56B*aJphh7 'hBF5B*aJphh7 'hnL5B*aJphh/h`86B*aJphh@<6B*aJphhnMB*aJphhnMhnM>*B*aJphss)s6sCslaSS $$Ifa$gd7 'K$ $Ifgd&cK$kd,$IfK$L$lFu!~Z t0    44 layt CsDsXsiszslaSS $$Ifa$gd7 'K$ $Ifgd&cK$kd-$IfK$L$lFu!~Z t0    44 layt zs{ssssslcXJJ $$Ifa$gd7 'K$ $Ifgd&cK$ $Ifgd&ckdk.$IfK$L$lFu!~Z t0    44 layt ssssssssssstt?t@t_t`tsttt|t}ttttttttttttttttttttt!u׺亭ǠננǠננǓדדzmhz#AhT%B*CJphhT%B*aJphh7 'hdB*H*aJphh7 'hdB*aJphh7 'h&cB*aJphhz#AhnLB*CJphhz#Ah@<B*CJphh7 'hT%56B*aJphh7 'hnLB*aJphh7 'h@<B*aJphh7 'h@<>*B*aJph)ssss tt t!t,tlcccXLLL $$Ifa$gd7 ' $Ifgd&cK$ $Ifgd&ckd"/$IfK$L$lFu!~Z t0    44 layt ,t6t?t@tAtLtVt_t`tRkd/$IfK$L$lFu!~Z t0    44 layt $$Ifa$gd7 'K$ $$Ifa$gd7 '`ttt}ttttttSkd0$IfK$L$lFu!~Z t0    44 layt $$Ifa$gd7 'K$ $Ifgd&cK$tttttlaSS $$Ifa$gd7 'K$ $Ifgd&cK$kdG1$IfK$L$lFu!~Z t0    44 layt tttt uu"u#u(ulccccXLL $$Ifa$gdT% $Ifgd&cK$ $Ifgd&ckd1$IfK$L$lFu!~Z t0    44 layt !u"uGuKuLuMu^u_udufuguiujukulupuuuuuuȾ~q~bUEhL[]h>P56B*aJphh\>AhOXlB*aJphh=dh>P5B*aJphhxh>PB*aJphhxB*aJphh7 'h:i56B*aJphhz#Ah:iB*CJphh:iB*CJphh=dh=dB*H*aJphh:iB*aJphh7 'hT%56B*aJphhz#AhsB*CJphhz#AhT%B*CJphh7 'hT%B*aJph(u-u2u7u8u=uBuGuLu $$Ifa$gd7 'K$ $$Ifa$gd7 ' $$Ifa$gdT%K$ $$Ifa$gdT%LuMudugujulaSE $$Ifa$gd7 'K$ $$Ifa$gdT%K$ $Ifgd&cK$kd2$IfK$L$lFu!~Z t0    44 layt jukuuuulcZL $$Ifa$gdL[]K$ $Ifgd=Y $Ifgd=dkdl3$IfK$L$lFu!~Z t0    44 layt uu7v $$Ifa$gdL[]K$lkd#4$IfK$L$l !! t0!44 layt uuBvCvNvOvovqvsvvvvvvvvvvvvvvvwwwwwww#w+w2wLwMw[w\wwwwwwww=x>x?x@x˾վվվմվվվվվվվh=Y5B*aJphh*h1xB*CJaJphhQh1xB*CJphhxB*CJphh,B*aJphh*h>PB*aJphh TeB*aJphh*h1xB*aJphhL[]h1x5B*aJphhL[]h>P5B*aJph/7v8vCvOv[vevpvxj $$Ifa$gd TeK$ $$Ifa$gd Te $$Ifa$gdL[]K$lkd4$IfK$L$l !! t0!44 layt pvqvvvvvYN@@@ $$Ifa$gdL[]K$ $Ifgd>PK$kd95$IfK$L$l\)!FL t0!44 layt vvvvwwYN@@@ $$Ifa$gdL[]K$ $Ifgd>PK$kd6$IfK$L$l \)!FL t0!44 layt www+w9w?wMwYPPPPE $Ifgd>PK$ $Ifgd>Pkd6$IfK$L$l \)!FL t0!44 layt Mw\wkwxwwwwwwwwwxx*x>x $$Ifa$gdL[]K$ $$Ifa$gdL[]>x?x@xxxYLC8 $IfgdOXlK$ $IfgdOXl h$If^hgd=Ykd7$IfK$L$l\)!FL t0!44 layt @xxxxxxyyyy!y/y0y$IfK$L$l\ u!xxxy t044 laytzzzz{ {\QCCC $$Ifa$gdK$ $IfgdOXlK$kd%?$IfK$L$l\ u!xxxy t044 layt { {{"{-{0{\QCCC $$Ifa$gdK$ $IfgdOXlK$kd?$IfK$L$l\ u!xxxy t044 layt0{1{={J{U{X{\QCCC $$Ifa$gdK$ $IfgdOXlK$kd}@$IfK$L$l\ u!xxxy t044 laytX{Y{Z{{{{{\SSH<< $$Ifa$gd $IfgdK$ $IfgdOXlkd)A$IfK$L$l\ u!xxxy t044 laytY{Z{{2|5|6|h|i|||||||}B}E}F}q}w}x}y}|}}}}}}}}}}}}}0~1~l~m~|~~~~~~~~~~~~~~~ٿhh/gB*aJphhh05B*aJphhh0B*aJphhh{B5B*aJphhh{BB*aJphhhB*aJphhh5B*aJphh5B*aJphhYr5B*aJph5{{{{||| |DkdA$IfK$L$l\z!||}} t044 layt $$Ifa$gd $$Ifa$gdK$ |2|3|4|5|6|9|H|SE $$Ifa$gdK$kdxB$IfK$L$l\z!||}} t044 layt $IfgdK$H|W|h|i|m|{|||PE $IfgdK$kdC$IfK$L$l\z!||}} t044 layt $$Ifa$gdK$||||||^SSSS $IfgdK$kdC$IfK$L$l\z!||}} t044 layt||||||^SEEE $$Ifa$gdK$ $IfgdK$kdaD$IfK$L$l\z!||}} t044 layt||||}}^SEEE $$Ifa$gdK$ $IfgdK$kdE$IfK$L$l\z!||}} t044 layt}}B}C}D}E}^SSSS $IfgdK$kdE$IfK$L$l\z!||}} t044 laytE}F}J}Y}h}x}^SEEE $$Ifa$gdK$ $IfgdK$kdJF$IfK$L$l\z!||}} t044 laytx}y}|}}}}^SEEE $$Ifa$gdK$ $IfgdK$kdF$IfK$L$l\z!||}} t044 layt}}}}}}^SEEE $$Ifa$gdK$ $IfgdK$kdG$IfK$L$l\z!||}} t044 layt}}}}}}^SEEE $$Ifa$gdK$ $IfgdK$kd3H$IfK$L$l\z!||}} t044 layt}}~~~0~^SEEE $$Ifa$gdK$ $IfgdK$kdH$IfK$L$l\z!||}} t044 layt0~1~@~M~Z~l~^SEEE $$Ifa$gdK$ $IfgdK$kdyI$IfK$L$l\z!||}} t044 laytl~m~|~~~~^SEEE $$Ifa$gdK$ $IfgdK$kdJ$IfK$L$l\z!||}} t044 layt~~~~~~^SEEE $$Ifa$gdK$ $IfgdK$kdJ$IfK$L$l\z!||}} t044 layt~~~~P^UL?? & F$Ifgd $Ifgd=Y $Ifgd=dkdbK$IfK$L$l\z!||}} t044 layt~~~~NOP '*ɿzqhqhbXQXH> *h4>h,aJh,h JsaJ h,5aJh,h,5aJ h,aJhqh JsaJhqhxaJ hqaJh Jsh JsaJ h JsaJh Jsh Js5aJ hQaJhOXlh JsB*aJphhOXlh JsaJhOXlB*aJphh,B*aJphh>Ph=YB*aJphh=Y5B*aJphh=YhvJ5B*aJphhh05B*aJph[? & F $7$8$H$Ifgd $7$8$H$Ifgdq$7$8$H$If^gd,$7$8$H$If^gdx & F$7$8$H$Ifgd $7$8$H$Ifgd, $7$8$H$Ifgd=Y <@i >?MNo҄ "#$ن"8ڸyyyqh4>OJQJh' OJQJhOJQJhGOJQJhhOJQJhhLCJOJQJaJh_OhLB*aJphhqhLaJhOXlhqaJ hqaJhqh Js>*aJhOXlh JsaJhqhqaJhqh JsaJhqh Js5aJ,$9l[[[[ & F $7$8$H$Ifgd  & F $1$7$8$H$Ifgd $IfgdvkdL$$Ifl0("0(4 lalyt 89:CSTڇ[wxyznopqrz{ɉىډȿȿȿȿxi]iNh5CJH*OJQJaJhcCJOJQJaJh_Oh/CJOJQJaJh/CJOJQJaJhmCJOJQJaJ h`8aJ h~SaJhhLB*aJphh/h5aJ h' aJ h4>aJhhaJ h5aJhh5aJhchLCJOJQJaJh_OhLB*aJphh=YhLOJQJ9:CTۇ܇zoq``qqOO & F $7$8$H$Ifgd  & F $7$8$H$Ifgd $7$8$H$Ifgd $IfgdvkdL$$Ifl0("0(4 lalyt opqrstuvwxyzۉ{$Ifgd TevkdUM$$Ifl0("0(4 lalyt ډۉNJ+Pghiq~丮䑄whVhGhVhh=Y>*CJOJQJ\aJ"h)}h=Y>*CJOJQJ\aJh)}h=YCJOJQJaJh=Y5CJOJQJaJhXq>*CJOJQJaJhJBhXq>*CJOJQJaJhJBh VB*aJphh=YB*aJphh~+B*aJphhJBhcaJhJBhc6aJhJBhKGaJ h?&aJhJBhc5aJ"h TehKG5CJH*OJQJaJhvpg $Ifgd=Y$IfkdM$$Ifl0& t0644 laytK $Ifgd?&hiqjbynaTTTK $Ifgd=Y  & F$Ifgd  & F$Ifgd $Ifgd?&$IfkdN$$Ifl0& t0644 laytKċŋƋhijkތ%abⵦ{l{{l\M>h4h4CJOJQJaJhJBh4CJOJQJaJh4h)}5CJOJQJaJh4h~CJOJQJaJh4hXqCJOJQJaJh4h45CJOJQJaJh4CJOJQJaJhJBhXqCJOJQJaJh4h=YCJOJQJaJh=YCJOJQJaJ"h)}h=Y5CJOJQJ\aJh)}h=YCJOJQJaJh=Y>*CJOJQJ\aJǍȍʍ[\owIJKL_`ĸĩКtdtdUFFh=Yh:CJOJQJaJhJBh:CJOJQJaJhJBh:5CJOJQJaJh~+5CJOJQJaJh=Y5CJOJQJaJh~+CJOJQJaJhJBh4CJOJQJaJhJBh~CJOJQJaJh4CJOJQJaJh=YCJOJQJaJhJBhXqCJOJQJaJ"hJBhXq56CJOJQJaJh=Y56CJOJQJaJɍ[\KL`vӏ*;  & F$Ifgd $IfgdXq 8$If^8gd4  & F$Ifgd h$If^hgd4 $Ifgd4  & F$Ifgd $Ifgd=Y`ovɏҏӏ )*:;tµrfrWrJh' h@20B*aJphh' h@20CJOJQJaJh4CJOJQJaJh' hXqCJOJQJaJ"hJBhXq56CJOJQJaJ"hJBhXq5>*CJOJQJaJh4h45CJOJQJaJhS5CJOJQJaJhJBhXq5CJOJQJaJhJBhXqCJOJQJaJhJBh |5CJOJQJaJhJBh |CJOJQJaJ;,\{1m4C'  & F$Ifgd $IfgdXq  & F$Ifgd  & F$Ifgd $Ifgd4 & F $Ifgd  & F$Ifgd  & F$Ifgd +AlmܒrcSD5h~+h~+CJOJQJaJh~+h4CJOJQJaJh~+h~+5CJOJQJaJh~+56CJOJQJaJhJBh4>*CJOJQJaJh~+CJOJQJaJhJBh46CJOJQJaJhJBh4CJOJQJaJ"hJBh456CJOJQJaJh@20B*aJphh' hXqB*aJphhYrB*aJphh' h@20B*aJphh4B*aJphhJBh4aJ34CU !%&'(߿viZKZKi;2hJBhcaJh' hc5CJOJQJaJh' hSCJOJQJaJh' hXqCJOJQJaJh' 5CJOJQJaJhJBh' CJOJQJaJh' CJOJQJaJhJBhSCJOJQJaJhJBhXqCJOJQJaJhJBhXq>*CJOJQJaJh4h45CJOJQJaJhJBh46CJOJQJaJhJBh4CJOJQJaJ"h~+h456CJOJQJaJ'(1E^Õyyllllcc $Ifgd & F $Ifgd $Ifkd.O$$Ifl0& t0644 laytK (1ELMԕՕ"#fhޖߖ&,;<BOPu~Řʘ٘#TXcwxɹðɹɹɰxohJBhGaJhJBh>*aJhJBh6]aJh`8haJ h`8aJhJBhaJhJBh5aJh' haJh' h@20H*aJ h4aJh' h@20aJ h' aJhJBh@20>*aJhJBh@20aJhJBh@205aJhJBhc5aJ+%٘wߙxpjb & F$Ifgd ݛ#$Jij}~̜Ԝݜ!"#/0Labckvʝӝ詠Ɔ}hgh aJ h~aJh`8h`85aJhJBhc5aJhJBhcaJh' h@20aJh' hG>*aJh' hGH*aJ h`8aJh' hH*aJhJBhGaJhJBhaJh' haJh' hGaJ h' aJ.bckvʝ%&ypccVVI 8$If^8gdp & F$Ifgd & F$Ifgd $Ifgd`8$IfkdO$$Ifl0& t0644 laytKӝ$%&:;<BCmnĞ()ßҟӟԟ)ŻŵŻŻů▩|||vlchKh[aJhKh[5aJ h[aJhF|hF|aJ hF|6aJhF|hF|6aJhphpaJhkhp6aJ hF|aJ h`8aJ h~aJhkhk>*aJ hkaJh~h~aJ hsl5aJ h~5aJ hpaJ hgaJhghcaJhghgaJ$&<n)xӟԟ $$Ifa$gdF4K$ $Ifgd[ & F$Ifgd & F$Ifgd $Ifgd' /9Ek_QQQ $$Ifa$gdF4K$ $$Ifa$gdF4kdfP$IfK$L$lF $$ 5  t06    44 laytK)*23>?`behjݠޠߠ+,-9@AIJRTux{ǡȡɡʡۡܡ23 hsl5CJhghsl5CJhghslaJhghsl5aJ h[5aJ hsl5aJ hp5aJhN=h[CJhgh[CJ h[CJ h[aJhKh[aJhKh[>*aJ8EFjkbbbWKKK $$Ifa$gdF4 $IfgdpK$ $Ifgdpkd Q$IfK$L$lF $$ 5  t06    44 laytKˠՠޠߠQkdQ$IfK$L$lF $$ 5  t06    44 laytK $$Ifa$gdF4K$ $$Ifa$gdF4ߠ !, $$Ifa$gdF4K$ $$Ifa$gdF4 $IfgdpK$ $Ifgdp $Ifgd Te ,-AJSk`RR $$Ifa$gdF4K$ $IfgdpK$kdR$IfK$L$lF $$ 5  t06    44 laytKST|kbbWKKK $$Ifa$gdF4 $IfgdpK$ $IfgdpkdNS$IfK$L$lF $$ 5  t06    44 laytKȡɡʡܡQHH $IfgdpkdT$IfK$L$lF $$ 5  t06    44 laytK $$Ifa$gdF4 $$Ifa$gdF4K$ܡ03IOehoww $$Ifa$gd nkdT$IfK$L$lJ7 t0644 layt@ $$Ifa$gd K$ 3INOeop¢345DETUde c|ĤŤƤǤݿ~w~wqh~whvJhpaJ hvJaJ hvJ6aJhghvJ6aJhghpB*aJphhghp6aJhghpaJ hvJ5aJhghp5aJ h[aJhoShslaJ h TeCJ h@CJhghslCJhghslaJ hsl5CJhghsl5CJh Teh TeCJ(opE77777 $$Ifa$gd K$kdPU$IfK$L$lrW KJDTB t0644 layt@¢עE77777 $$Ifa$gd K$kd6V$IfK$L$lrW KJDTB t0644 layt@5@EE<1% $$Ifa$gd $Ifgd@K$ $Ifgd@kdW$IfK$L$lrW KJDTB t0644 layt@EPU`epu $$Ifa$gdL K$ $$Ifa$gd $$Ifa$gd K$E<3% $$Ifa$gdpK$ $Ifgd[ $IfgdpkdX$IfK$L$lrW KJDTB t0644 layt@.@HZbznznz $$Ifa$gdp $$Ifa$gdpK$wkdX$IfK$L$l~mZ t 6`0644 lae4ytKbc|bYNBB $$Ifa$gdp $IfgdpK$ $IfgdpkdY$IfK$L$l~F Aml , t 6`06    44 lae4ytKŤH? $IfgdpkdTZ$IfK$L$l~F Aml , t 6`06    44 lae4ytK $$Ifa$gdp $$Ifa$gdpK$ǤΤϤФԤդ֤5Pkǥȥ˥'0178ʩdrzpzpfhYrB*aJphh[B*aJphhah[B*aJphh[5B*aJphh.B*aJphhgh[>*aJ hKaJhgh[aJhgh[5aJhghL aJhghL 6aJhghp6aJhghpaJ hvJaJhghvJaJhghvJ6aJ"Ť֤=kd [$IfK$L$l~F Aml , t 6`06    44 lae4ytK $$Ifa$gdpK$ $$Ifa$gdp $IfgdpK$'45P]jIkd[$IfK$L$l~F Aml , t 6`06    44 lae4ytK $$Ifa$gdpK$ $IfgdpK$jkbWII $$Ifa$gdpK$ $IfgdpK$kd\$IfK$L$l~F Aml , t 6`06    44 lae4ytKƥbWII $$Ifa$gdpK$ $IfgdpK$kd]$IfK$L$l~F Aml , t 6`06    44 lae4ytKƥǥȥɥʥbWII $$Ifa$gdpK$ $IfgdpK$kdP^$IfK$L$l F Aml ,  t 6`06    44 lae4ytL ʥ˥'bT $$Ifa$gdF4K$kd*_$IfK$L$l F Aml , t 6`06    44 lae4ytL '(1=IP $$Ifa$gdF4K$nkd`$IfK$L$l t0644 laytKPQ\iv{ZLLL@L $$Ifa$gdF4 $$Ifa$gdF4K$kd`$IfK$L$l\ {||~ t0644 laytKȦZLLL@L $$Ifa$gdF4 $$Ifa$gdF4K$kdOa$IfK$L$l\ {||~ t0644 laytKȦɦ֦ZLLL@L $$Ifa$gdF4 $$Ifa$gdF4K$kd b$IfK$L$l\ {||~ t0644 laytK $3BGUZLLL@L $$Ifa$gdF4 $$Ifa$gdF4K$kdb$IfK$L$l\ {||~ t0644 laytKUVwZLLL@L $$Ifa$gdF4 $$Ifa$gdF4K$kdc$IfK$L$l\ {||~ t0644 laytKŧԧ٧ZLLL@L $$Ifa$gdF4 $$Ifa$gdF4K$kdCd$IfK$L$l\ {||~ t0644 laytK*ZLLL@L $$Ifa$gdF4 $$Ifa$gdF4K$kde$IfK$L$l\ {||~ t0644 laytK*+:HV[jZLLL@L $$Ifa$gdF4 $$Ifa$gdF4K$kde$IfK$L$l\ {||~ t0644 laytKjkèZN@@@N@ $$Ifa$gdF4K$ $$Ifa$gdF4kdzf$IfK$L$l\ {||~ t0644 laytKèĨߨ ZN@@@N@ $$Ifa$gdF4K$ $$Ifa$gdF4kd7g$IfK$L$l\ {||~ t0644 laytK8ZQQD77 & F$Ifgd & F$Ifgd $Ifgd.kdg$IfK$L$l\ {||~ t0644 laytKst9rl_R & F$Ifgd & F$Ifgd $Ifkdh$$Ifl0& t0644 laytK & F$Ifgd rstjv  HVz   "#߿{w{w{w{wnja[ h'CJh'6CJ]h'h'5CJ\h)jh)UhhcaJh Dh~B*aJphh DB*aJphh9B*aJph h[5aJUhh[aJhJBh[5aJhphcaJ h[6aJ h[aJhJBhc5aJhJBhcaJh(thgB*aJph# IVyp__pR & F$Ifgd  & F $7$8$H$Ifgd $Ifgd[$IfkdMi$$Ifl0& t0644 laytKative study Baseline characteristics were comparable between both groups Limitations: Ceftaroline lacks in vitro activity against atypical organisms, which are recommended for empiric coverage for the treatment of CAP according to the IDSA guidelines.     Ceftaroline Monograph Updated version may be found at  HYPERLINK "http://www.pbm.va.gov" www.pbm.va.gov or vaww.pbm.va.gov PAGE 1     }}}}}}}}}tn$If $IfgdLkdi$$Iflo0& t0644 laytK #$%&'() $$Ifa$$Ifbkdj$$IflF<' 6    4 laytx $$Ifa$)*{rlc $$Ifa$$If $IfgdRekdk$$IflF<'S t06    4 la#*JKno}~hhcaJhALh)h$ 0JmHnHu h'0Jjh'0JUhdh'0J6]jh'6U] h'6]h'{ywwwwwwwwkdk$$IflF<'S t06    4 la 6&P1+:p9/ =!"#$%] $$If!vh5t5#vt#v:V l t065t5yt)oQ$$If!vh5t5#vt#v:V l t065t5yt)oQ$$If!vh5t5#vt#v:V l t065t5yt)oQ$$If!vh5t5#vt#v:V l t065t5yt)oQ$$If!vh5t5#vt#v:V l t065t5yt)oQ$$If!vh5t5#vt#v:V l t065t5yt)oQ$$If!vh5t5#vt#v:V l t065t5yt)oQ$$If!vh5t5#vt#v:V l  t065t5yt)oQ$$If!vh55 #v#v :V l t0655 / yts$$If!vh55 #v#v :V l t0655 / yts$$If!vh55 #v#v :V l t0655 / yts$$If!vh55 #v#v :V l t0655 / yts$$If!vh55 #v#v :V l t0655 / yts$$If!vh55 #v#v :V l t0655 / yts$$If!vh55 #v#v :V l t0655 / yts$$If!vh55 #v#v :V l t0655 / ytn$$If!vh55 #v#v :V l t0655 / ytswDyK yK http://vaww.national.cmop.va.gov/PBM/Directives Policies and Information Letters/Guidance on Off Label Prescribing.pdfyX;H,]ą'c$$If!vh55#v#v:V l0655yt:A$$If!vh55#v#v:V l0655yt:A$$If!vh55#v#v:V l0655yt:A$$If!vh55#v#v:V l0655yt:A$$If!vh55#v#v:V l0655yt:A$$If!vh5 5= 5 5#v #v= #v #v:V l t065 5e 5K 5 ytS $$If!vh5 5= 5 5#v #v= #v #v:V l t065 5e 5K 5 ytS $$If!vh5 5= 5 5#v #v= #v #v:V l t065 5e 5K 5 ytS $$If!vh5 5= 5 5#v #v= #v #v:V l t065 5e 5K 5 ytS $$If!vh5 5= 5 5#v #v= #v #v:V l t065 5e 5K 5 ytS $$If!vh5 5= 5 5#v #v= #v #v:V l t065 5e 5K 5 ytS $$If!vh5 5= 5 5#v #v= #v #v:V l t065 5e 5K 5 ytS $$If!vh5 5e 5K 5 #v #ve #vK #v :V l t065 5e 5K 5 ytS $$If!vh5 5e 5K 5 #v #ve #vK #v :V l t065 5e 5K 5 ytS $$If!vh5 5e 5K 5 #v #ve #vK #v :V l t065 5e 5K 5 ytS $$If!vh5 5e 5K 5 #v #ve #vK #v :V l t065 5e 5K 5 ytS $$If!vh5 5e 5K 5 #v #ve #vK #v :V l t065 5e 5K 5 ytS $$If!vh5 5e 5K 5 #v #ve #vK #v :V l t065 5e 5K 5 ytS $$If!vh5 5e 5K 5 #v #ve #vK #v :V l t065 5e 5K 5 ytS $$If!vh5 5 5 #v :V l t065 ytnk#$$If!vh5 5 5 #v :V l t065 ytnk#$$If!vh5 5 5 #v :V l t065 ytnk#$$If!vh5 5 5 #v :V l t065 ytnk#$$If!vh5 5 5 #v :V l t065 ytnk#$$If!vh5 5 5 #v :V l t065 ytnk#$$If!vh5 5 5 #v :V l t065 ytnk#$$If!vh5 5 5 #v :V l t065 ytnk#$$If!vh5 5 5 #v :V l t065 ytnk#$$If!vh5g 565555R#vg #v6#v#v#v#vR:V   t<55555d55,/ /  / 22 l4 p<yt$$If!vh5g 565555R#vg #v6#v#v#v#vR:V o t55555d55,/ / /  22 l4 yt$$If!vh5 5 55 #v #v #v#v :V l05 5 55 4ytE\$$If!vh5 5 55 #v #v #v#v :V l05 5 55 4ytE\$$If!vh5"#v":V l05"4yt' $$If!vh5 5 55 #v #v #v#v :V l105 5 55 4yt%S$$If!vh5 5 55 #v #v #v#v :V l05 5 55 4ytE\$$If!vh5 5 55 #v #v #v#v :V l05 5 55 4ytE\$$If!vh5 5 55 #v #v #v#v :V l05 5 55 4ytE\$$If!vh5 5 55 #v #v #v#v :V l05 5 55 4ytE\$$If!vh5"#v":V l05"4yt' $$If!vh5 5 55 #v #v #v#v :V l05 5 55 4ytE\$$If!vh5 5 55 #v #v #v#v :V l05 5 55 4ytE\$$If!vh5 5 55 #v #v #v#v :V l05 5 55 4ytE\$$If!vh5 5 55 #v #v #v#v :V l05 5 55 4ytE\$$Ifl!vh55"#v#v":V l 0(55"4alyt $$Ifl!vh55"#v#v":V l0(55"4alyt $$Ifl!vh55"#v#v":V l,0(55"4alyt $$Ifl!vh55"#v#v":V l0(55"4alyt $IfK$L$!vh55~5Z#v#v~#vZ:V l t055~5Zayt $IfK$L$!vh55~5Z#v#v~#vZ:V l t055~5Zayt $IfK$L$!vh55~5Z#v#v~#vZ:V l t055~5Zayt $IfK$L$!vh55~5Z#v#v~#vZ:V l t055~5Zayt $IfK$L$!vh55~5Z#v#v~#vZ:V l t055~5Zayt $IfK$L$!vh55~5Z#v#v~#vZ:V l t055~5Zayt $IfK$L$!vh55~5Z#v#v~#vZ:V l t055~5Zayt $IfK$L$!vh55~5Z#v#v~#vZ:V l t055~5Zayt $IfK$L$!vh55~5Z#v#v~#vZ:V l t055~5Zayt $IfK$L$!vh55~5Z#v#v~#vZ:V l t055~5Zayt $IfK$L$!vh5!#v!:V l  t0!5!ayt $IfK$L$!vh5!#v!:V l  t0!5!ayt $IfK$L$!vh55F55L #v#vF#v#vL :V l t0!55F55L ayt $IfK$L$!vh55F55L #v#vF#v#vL :V l  t0!55F55L ayt $IfK$L$!vh55F55L #v#vF#v#vL :V l  t0!55F55L ayt $IfK$L$!vh55F55L #v#vF#v#vL :V l t0!55F55L ayt $IfK$L$y!vh5x5x5x5y#vx#vy:V l t05x5yayt$IfK$L$y!vh5x5x5x5y#vx#vy:V l t05x5yayt$IfK$L$y!vh5x5x5x5y#vx#vy:V l t05x5yayt$IfK$L$y!vh5x5x5x5y#vx#vy:V l t05x5yayt$IfK$L$y!vh5x5x5x5y#vx#vy:V l t05x5yayt$IfK$L$y!vh5x5x5x5y#vx#vy:V l t05x5yayt$IfK$L$y!vh5x5x5x5y#vx#vy:V l t05x5yayt$IfK$L$y!vh5x5x5x5y#vx#vy:V l t05x5yayt$IfK$L$y!vh5x5x5x5y#vx#vy:V l t05x5yayt$IfK$L$y!vh5x5x5x5y#vx#vy:V l t05x5yayt$IfK$L$y!vh5x5x5x5y#vx#vy:V l t05x5yayt$IfK$L$y!vh5x5x5x5y#vx#vy:V l t05x5yayt$IfK$L$y!vh5x5x5x5y#vx#vy:V l t05x5yayt$IfK$L$y!vh5x5x5x5y#vx#vy:V l t05x5yayt$IfK$L$q!vh5|5|5}5}#v|#v}:V l t05|5}yt$IfK$L$q!vh5|5|5}5}#v|#v}:V l t05|5}yt$IfK$L$q!vh5|5|5}5}#v|#v}:V l t05|5}yt$IfK$L$q!vh5|5|5}5}#v|#v}:V l t05|5}yt$IfK$L$q!vh5|5|5}5}#v|#v}:V l t05|5}yt$IfK$L$q!vh5|5|5}5}#v|#v}:V l t05|5}yt$IfK$L$q!vh5|5|5}5}#v|#v}:V l t05|5}yt$IfK$L$q!vh5|5|5}5}#v|#v}:V l t05|5}yt$IfK$L$q!vh5|5|5}5}#v|#v}:V l t05|5}yt$IfK$L$q!vh5|5|5}5}#v|#v}:V l t05|5}yt$IfK$L$q!vh5|5|5}5}#v|#v}:V l t05|5}yt$IfK$L$q!vh5|5|5}5}#v|#v}:V l t05|5}yt$IfK$L$q!vh5|5|5}5}#v|#v}:V l t05|5}yt$IfK$L$q!vh5|5|5}5}#v|#v}:V l t05|5}yt$IfK$L$q!vh5|5|5}5}#v|#v}:V l t05|5}yt$IfK$L$q!vh5|5|5}5}#v|#v}:V l t05|5}yt$$Ifl!vh55"#v#v":V l0(55"/ 4alyt $$Ifl!vh55"#v#v":V l0(55"4alyt $$Ifl!vh55"#v#v":V l0(55"4alyt $$If!vh55 #v#v :V l t0655 ytK$$If!vh55 #v#v :V l t0655 ytK$$If!vh55 #v#v :V l t0655 ytK$$If!vh55 #v#v :V l t0655 ytK$IfK$L$!vh5 55 5 #v #v5 #v :V l t065 55 5 aytK$IfK$L$!vh5 55 5 #v #v5 #v :V l t065 55 5 aytK$IfK$L$!vh5 55 5 #v #v5 #v :V l t065 55 5 aytK$IfK$L$!vh5 55 5 #v #v5 #v :V l t065 55 5 aytK$IfK$L$!vh5 55 5 #v #v5 #v :V l t065 55 5 aytK$IfK$L$!vh5 55 5 #v #v5 #v :V l t065 55 5 aytK$IfK$L$!vh57#v7:V l t0657ayt@$IfK$L$!vh5D5T555B#vD#vT#v#v#vB:V l t065D5T555Bayt@$IfK$L$!vh5D5T555B#vD#vT#v#v#vB:V l t065D5T555Bayt@$IfK$L$!vh5D5T555B#vD#vT#v#v#vB:V l t065D5T555Bayt@$IfK$L$!vh5D5T555B#vD#vT#v#v#vB:V l t065D5T555Bayt@$IfK$L$!vh5Z#vZ:V l~ t 6`065Zae4ytK$IfK$L$!vh5l 55, #vl #v#v, :V l~ t 6`065l 55, ae4ytK$IfK$L$!vh5l 55, #vl #v#v, :V l~ t 6`065l 55, ae4ytK$IfK$L$!vh5l 55, #vl #v#v, :V l~ t 6`065l 55, ae4ytK$IfK$L$!vh5l 55, #vl #v#v, :V l~ t 6`065l 55, ae4ytK$IfK$L$!vh5l 55, #vl #v#v, :V l~ t 6`065l 55, ae4ytK$IfK$L$!vh5l 55, #vl #v#v, :V l~ t 6`065l 55, ae4ytK$IfK$L$!vh5l 55, #vl #v#v, :V l  t 6`065l 55, / ae4ytL $IfK$L$!vh5l 55, #vl #v#v, :V l  t 6`065l 55, / ae4ytL $IfK$L$!vh5#v:V l t065aytK$IfK$L$!vh5{5|5|5#v{#v|#v:V l t065{5|5~aytK$IfK$L$!vh5{5|5|5#v{#v|#v:V l t065{5|5~aytK$IfK$L$!vh5{5|5|5#v{#v|#v:V l t065{5|5~aytK$IfK$L$!vh5{5|5|5#v{#v|#v:V l t065{5|5~aytK$IfK$L$!vh5{5|5|5#v{#v|#v:V l t065{5|5~aytK$IfK$L$!vh5{5|5|5#v{#v|#v:V l t065{5|5~aytK$IfK$L$!vh5{5|5|5#v{#v|#v:V l t065{5|5~aytK$IfK$L$!vh5{5|5|5#v{#v|#v:V l t065{5|5~aytK$IfK$L$!vh5{5|5|5#v{#v|#v:V l t065{5|5~aytK$IfK$L$!vh5{5|5|5#v{#v|#v:V l t065{5|5~aytK$IfK$L$!vh5{5|5|5#v{#v|#v:V l t065{5|5~aytK$$If!vh55 #v#v :V l t0655 ytK$$If!vh55 #v#v :V l t0655 ytK$$If!vh55 #v#v :V lo t0655 ytK|$$If!vh5C575.#vC#v7#v.:V l65 554ytx$$If!vh5555V#v#v5#vV:V l t065S554$$If!vh5555V#v#v5#vV:V l t065S554^4 002 0@P`p2( 0@P`p 0@P`p 0@P`p 0@P`p 0@P`p 0@P`p8XV~_HmH nH sH tH <`< xNormalCJ_HmH sH tH J@J $U Q Heading 1$xx@&5>*OJQJL@L  Heading 2$x@&5CJOJQJ88  Heading 3$@&5@@  Heading 4$@& 6B*phL@RL  Heading 7$<@&5CJOJQJ88  Heading 8$@&5DA`D Default Paragraph FontVi@V  Table Normal :V 44 la (k (No List @>@@ Title$a$5B*OJQJphJJ@J Subtitle$a$5B*CJOJQJph:B@: % Body Text CJOJQJ:":  Footnote TextCJ0U@10 Hyperlink>*B*4@B4 Header  !8OR8 Table B*CJph>6b> ~ List Bullet 2  & F@ @r@ Footer  ! CJOJQJ.)@. Page NumberHH % Balloon TextCJOJQJ^JaJ6Q6 TableFootnoteD"@D Caption $x5CJOJQJ\^O^ `Style Heading 1 + Black xx B*\phFVF NFollowedHyperlink >*B* phT^@T &{ Normal (Web)dd[$\$B* CJaJphjj nL Table Grid7:V0T`T  No Spacing $CJOJPJQJ_HaJmH sH tH   KGname*!* KG xref-sep2@2@ Xq List Paragraph #^FAF MdHeading 1 Char5>*CJOJQJ<Q< MdBody Text CharOJQJVobV ^Default &7$8$H$!B*CJ_HaJmH phsH tH .Oab. ^0CM31' B*ph.ab. zS0CM35( B*ph.ab. zS0CM13) B*ph2ab2 z^0CM3*d B*ph.Oab. vAC0CM29+ B*ph$O$ |Zspelle>O> Sarticle-articlebodyB'B  W0Comment ReferenceCJaJ88 0 W0 Comment Text/CJ:: / W0Comment Text Char@j@ 2 WComment Subject15\F!F 1 WComment Subject Char5\@ 2@}0Revision3CJ_HmH sH tH PK![Content_Types].xmlj0Eжr(΢Iw},-j4 wP-t#bΙ{UTU^hd}㨫)*1P' ^W0)T9<l#$yi};~@(Hu* Dנz/0ǰ $ X3aZ,D0j~3߶b~i>3\`?/[G\!-Rk.sԻ..a濭?PK!֧6 _rels/.relsj0 }Q%v/C/}(h"O = C?hv=Ʌ%[xp{۵_Pѣ<1H0ORBdJE4b$q_6LR7`0̞O,En7Lib/SeеPK!kytheme/theme/themeManager.xml M @}w7c(EbˮCAǠҟ7՛K Y, e.|,H,lxɴIsQ}#Ր ֵ+!,^$j=GW)E+& 8PK!Ptheme/theme/theme1.xmlYOo6w toc'vuر-MniP@I}úama[إ4:lЯGRX^6؊>$ !)O^rC$y@/yH*񄴽)޵߻UDb`}"qۋJחX^)I`nEp)liV[]1M<OP6r=zgbIguSebORD۫qu gZo~ٺlAplxpT0+[}`jzAV2Fi@qv֬5\|ʜ̭NleXdsjcs7f W+Ն7`g ȘJj|h(KD- dXiJ؇(x$( :;˹! I_TS 1?E??ZBΪmU/?~xY'y5g&΋/ɋ>GMGeD3Vq%'#q$8K)fw9:ĵ x}rxwr:\TZaG*y8IjbRc|XŻǿI u3KGnD1NIBs RuK>V.EL+M2#'fi ~V vl{u8zH *:(W☕ ~JTe\O*tHGHY}KNP*ݾ˦TѼ9/#A7qZ$*c?qUnwN%Oi4 =3ڗP 1Pm \\9Mؓ2aD];Yt\[x]}Wr|]g- eW )6-rCSj id DЇAΜIqbJ#x꺃 6k#ASh&ʌt(Q%p%m&]caSl=X\P1Mh9MVdDAaVB[݈fJíP|8 քAV^f Hn- "d>znNJ ة>b&2vKyϼD:,AGm\nziÙ.uχYC6OMf3or$5NHT[XF64T,ќM0E)`#5XY`פ;%1U٥m;R>QD DcpU'&LE/pm%]8firS4d 7y\`JnίI R3U~7+׸#m qBiDi*L69mY&iHE=(K&N!V.KeLDĕ{D vEꦚdeNƟe(MN9ߜR6&3(a/DUz<{ˊYȳV)9Z[4^n5!J?Q3eBoCM m<.vpIYfZY_p[=al-Y}Nc͙ŋ4vfavl'SA8|*u{-ߟ0%M07%<ҍPK! ѐ'theme/theme/_rels/themeManager.xml.relsM 0wooӺ&݈Э5 6?$Q ,.aic21h:qm@RN;d`o7gK(M&$R(.1r'JЊT8V"AȻHu}|$b{P8g/]QAsم(#L[PK-![Content_Types].xmlPK-!֧6 +_rels/.relsPK-!kytheme/theme/themeManager.xmlPK-!Ptheme/theme/theme1.xmlPK-! ѐ' theme/theme/_rels/themeManager.xml.relsPK] 55 ((R ft-! "&')_,+.a03!5799="@CFHI N1P[QQRSTXU\acdg!jl(qrs!uu@x)zY{~8ډ`(ӝ)3Ǥr#VXYZ\cfghqstvwz~  "+?FS<v"b##^$$$P%%&,80\000'1n477P77778[88899H99<\@l@z@@@@@@@FOP PeP\QQ=RoRRS2SwSSSTLTTXbcf%iRmpsCszss,t`ttt(uLujuu7vpvvwMw>xxx0yyyyzMzzzzz {0{X{{ |H||||}E}x}}}}0~l~~~9oh;'b&Eߠ,SܡoEbŤjƥʥ'PȦU*jè )W[]^_`abdeijklmnopruxy{|}    !#$%&'()*,-./0123456789:;<=>@CDEGn(5XLpX!@   @  0(  B S  ?H0(  5 _Ref8050345366 j$ j$ jL$ j $ j# j# jL# j # jPPQ%QQQtUtU6PP$Q'QQQ{U{U68*urn:schemas-microsoft-com:office:smarttagsCity9*urn:schemas-microsoft-com:office:smarttagsState9 *urn:schemas-microsoft-com:office:smarttagsplaceB*urn:schemas-microsoft-com:office:smarttagscountry-region 4    :E KOgko{$V_(]a'2<MWdEQ} ~!!="G"{&&&&&&&&((((77R8[8::EEEE GGNGZGGGG H]HhHAIUIIIfJrJMNQNtN{NNNOO=P?PCPGPVPZPPPPPQ$QQQQQQQQQSSSST T TTTTTTTTVVW$WnYvYZZ["[O[V[\\__````!a,acctd}dhh*j,jjjjj kklln nn$n,n6n:YQQdfNo[nR_ Xnh(c'\.,s \_,E33a@dAaZ`:Ob|u{z-ʋ%}| ^`OJQJo(-hh^h`OJQJo(hHh8^8`OJQJ^Jo(hHoh^`OJQJo(hHh ^ `OJQJo(hHh ^ `OJQJ^Jo(hHohx^x`OJQJo(hHhH^H`OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHhh^h`OJQJo(hHh8^8`OJQJ^Jo(hHoh^`OJQJo(hHh ^ `OJQJo(hHh ^ `OJQJ^Jo(hHohx^x`OJQJo(hHhH^H`OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHh^`5CJaJo(phhH. ^`hH. pp^p`hH. @ @ ^@ `hH. ^`hH. ^`hH. ^`hH. ^`hH. PP^P`hH.hh^h`OJQJo(hHh8^8`OJQJ^Jo(hHoh^`OJQJo(hHh ^ `OJQJo(hHh ^ `OJQJ^Jo(hHohx^x`OJQJo(hHhH^H`OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHhh^h`OJQJo(hHh8^8`OJQJ^Jo(hHoh^`OJQJo(hHh ^ `OJQJo(hHh ^ `OJQJ^Jo(hHohx^x`OJQJo(hHhH^H`OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHh h^h`o(hH. 8^8`hH. L^`LhH.  ^ `hH.  ^ `hH. xL^x`LhH. H^H`hH. ^`hH. L^`LhH.hh^h`OJQJo(hHh8^8`OJQJ^Jo(hHoh^`OJQJo(hHh ^ `OJQJo(hHh ^ `OJQJ^Jo(hHohx^x`OJQJo(hHhH^H`OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHhh^h`OJQJo(hHh8^8`OJQJ^Jo(hHoh^`OJQJo(hHh ^ `OJQJo(hHh ^ `OJQJ^Jo(hHohx^x`OJQJo(hHhH^H`OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHhh^h`OJQJo(hHh8^8`OJQJ^Jo(hHoh^`OJQJo(hHh ^ `OJQJo(hHh ^ `OJQJ^Jo(hHohx^x`OJQJo(hHhH^H`OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHhh^h`OJQJo(hHh8^8`OJQJ^Jo(hHoh^`OJQJo(hHh ^ `OJQJo(hHh ^ `OJQJ^Jo(hHohx^x`OJQJo(hHhH^H`OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHhh^h`OJQJo(hHh8^8`OJQJ^Jo(hHoh^`OJQJo(hHh ^ `OJQJo(hHh ^ `OJQJ^Jo(hHohx^x`OJQJo(hHhH^H`OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHhh^h`OJQJo(hHh8^8`OJQJ^Jo(hHoh^`OJQJo(hHh ^ `OJQJo(hHh ^ `OJQJ^Jo(hHohx^x`OJQJo(hHhH^H`OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHhh^h`OJQJo(hHh8^8`OJQJ^Jo(hHoh^`OJQJo(hHh ^ `OJQJo(hHh ^ `OJQJ^Jo(hHohx^x`OJQJo(hHhH^H`OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHhh^h`OJQJo(hHh8^8`OJQJ^Jo(hHoh^`OJQJo(hHh ^ `OJQJo(hHh ^ `OJQJ^Jo(hHohx^x`OJQJo(hHhH^H`OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHhh^h`OJQJo(hHh8^8`OJQJ^Jo(hHoh^`OJQJo(hHh ^ `OJQJo(hHh ^ `OJQJ^Jo(hHohx^x`OJQJo(hHhH^H`OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHhh^h`OJQJo(hHh8^8`OJQJ^Jo(hHoh^`OJQJo(hHh ^ `OJQJo(hHh ^ `OJQJ^Jo(hHohx^x`OJQJo(hHhH^H`OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHhh^h`OJQJo(hHh8^8`OJQJ^Jo(hHoh^`OJQJo(hHh ^ `OJQJo(hHh ^ `OJQJ^Jo(hHohx^x`OJQJo(hHhH^H`OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHhh^h`OJQJo(hHh8^8`OJQJ^Jo(hHoh^`OJQJo(hHh ^ `OJQJo(hHh ^ `OJQJ^Jo(hHohx^x`OJQJo(hHhH^H`OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHhh^h`OJQJo(hHh8^8`OJQJ^Jo(hHoh^`OJQJo(hHh ^ `OJQJo(hHh ^ `OJQJ^Jo(hHohx^x`OJQJo(hHhH^H`OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHhh^h`OJQJo(hHh8^8`OJQJ^Jo(hHoh^`OJQJo(hHh ^ `OJQJo(hHh ^ `OJQJ^Jo(hHohx^x`OJQJo(hHhH^H`OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hH;h^h`OJPJQJ^Jo(-8^8`OJQJ^Jo(hHo^`OJQJo(hH ^ `OJQJo(hH ^ `OJQJ^Jo(hHox^x`OJQJo(hHH^H`OJQJo(hH^`OJQJ^Jo(hHo^`OJQJo(hHhh^h`OJQJo(hHh8^8`OJQJ^Jo(hHoh^`OJQJo(hHh ^ `OJQJo(hHh ^ `OJQJ^Jo(hHohx^x`OJQJo(hHhH^H`OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHhh^h`OJQJo(hHh8^8`OJQJ^Jo(hHoh^`OJQJo(hHh ^ `OJQJo(hHh ^ `OJQJ^Jo(hHohx^x`OJQJo(hHhH^H`OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHhh^h`OJQJo(hHh8^8`OJQJ^Jo(hHoh^`OJQJo(hHh ^ `OJQJo(hHh ^ `OJQJ^Jo(hHohx^x`OJQJo(hHhH^H`OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHhh^h`OJQJo(hHh8^8`OJQJ^Jo(hHoh^`OJQJo(hHh ^ `OJQJo(hHh ^ `OJQJ^Jo(hHohx^x`OJQJo(hHhH^H`OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHhh^h`OJQJo(hHh8^8`OJQJ^Jo(hHoh^`OJQJo(hHh ^ `OJQJo(hHh ^ `OJQJ^Jo(hHohx^x`OJQJo(hHhH^H`OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hH^`>*o() ^`hH. pL^p`LhH. @ ^@ `hH. ^`hH. L^`LhH. ^`hH. ^`hH. PL^P`LhH.hh^h`OJQJo(hHh8^8`OJQJ^Jo(hHoh^`OJQJo(hHh ^ `OJQJo(hHh ^ `OJQJ^Jo(hHohx^x`OJQJo(hHhH^H`OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHhh^h`OJQJo(hHh8^8`OJQJ^Jo(hHoh^`OJQJo(hHh ^ `OJQJo(hHh ^ `OJQJ^Jo(hHohx^x`OJQJo(hHhH^H`OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHhh^h`OJQJo(hHh8^8`OJQJ^Jo(hHoh^`OJQJo(hHh ^ `OJQJo(hHh ^ `OJQJ^Jo(hHohx^x`OJQJo(hHhH^H`OJQJo(hHh^`OJQJ^Jo(hHoh^`OJQJo(hHAaor:\c%};oyFHQ'\33a-a,r Om9!?.:YQ Xs \_rlp4"$$xl=/7{zbxF6c D:Obu[nRD50                                                                                                                                                                                     z                                                                                          mKTl1eE&XY&x02A?L Yx sX1xL YjbTlXY& dd`EwON?B@*1 o ),Mde q  3 H S R4~`TNu>f 2v)}9XLOyr*PXPndW 8d#nk#U$%T%V&7 '+Z'iy'w())o)*:+[+~+I-+b-A`.c%/c/@20rB07R0=2`4~4#6a7`8U:d]:D:<@<3C<E<->4>Pg>d?z#A:A\>A'B2CvAC DND7E ;GKG$IrI}vIvJ*kJS KALCLcLnL|MWN_O>PU Q)oQA~QRS%S1ZS~S +U VW&X!%X=Y*zY|Z[E\\\G-]L[]3^z^4^&`&c=dRe Tebef[f/gp5gpg$hZipi:i|GjtjkslOXljn*pXqq~q Js_es(tvt*u/#vx1xu{ ||1|st}~ !0I `!/@4x nMWiauFKWQQ6ECiz&{F|n>~Q9 00?`%hW+KN \~.][O'P !sYt8 *JBrS6\|L /N<k'%4*=Viev {:$ {BLU} %=)sGp?&}j[' ^W'NPqN$fYrV&Sx/t RF4Gyb 8cm'nO`:@ezSvI{dc8lDq+U6a{w3 s]zQKg5z BF"#X3A W@Am&Vv@L5@4@<@@UnknownG* Times New Roman5Symbol3. * Arial7.{ @Calibri5. *aTahoma?= * Courier New;WingdingsA BCambria Math"q hF BIS'BIS'!n24d88 3qHX ?%2!xx+National PBM Monograph Template Rev20091005 F. GoodmanEIE Desktop Technologies                          Oh+'0 4 Xd   ,National PBM Monograph Template Rev20091005 F. Goodman 02/10/05 Added legal statement Normal.dotmEIE Desktop Technologies6Microsoft Office Word@H'@ʶ)L@^{BI rd'S8 ,National PBM Monograph Template Rev20091005 Title(X` _PID_HLINKS_NewReviewCycleA }:whttp://vaww.national.cmop.va.gov/PBM/Directives Policies and Information Letters/Guidance on Off Label Prescribing.pdfl.http://www.pbm.va.gov/  !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~Root Entry FDj{Data Iel1TableWordDocument 8SummaryInformation(DocumentSummaryInformation8OMsoDataStore g{g{23EOCZKL25Q==2g{g{Item  Properties9CompObj yFWUURHUGJYAZF1==2 g{g{  !"#$%&'()*+,-./012345678:;<>?@BCDEFHIJLMNPQRSTUVWXYZ[\]_abc This value indicates the number of saves or revisions. The application is responsible for updating this value after each revision. xsd:documentation> xsd:annotation> me"/> DocumentLibraryFormDocumentLibraryFormDocumentLibraryForm ՜.+,D՜.+,d  hp  Hewlett-Packard'S8 ,National PBM Monograph Template Rev20091005 Title80t| _PID_HLINKS_NewReviewCycle ContentTypeA }:whttp://vaww.national.cmop.va.gov/PBM/Directives Policies and Information Letters/Guidance on Off Label Prescribing.pdfl.http://www.pbm.va.gov/ Document