Ceftaroline fosamil for treatment of community-acquired pneumonia: findings from FOCUS 1 and 2 and potential role in therapy

Cephalosporins have been widely used over the last few decades (often as first-line antibiotic therapy) for numerous infections, owing primarily to their broad spectrum of microbiologic activity and favorable safety profile. Current Infectious Diseases Society of America guidelines identify a third-generation cephalosporin in combination with a macrolide antibiotic as an option for treatment of hospitalized adult patients with community-acquired pneumonia (CAP) outside the intensive care unit setting. Although ceftriaxone is a frequently used agent for CAP, increasing incidence of multidrug-resistant Streptococcus pneumoniae and concerns regarding poor outcomes associated with ineffective therapy have prompted the search for a well-tolerated treatment alternative that is effective against bacteria that can cause CAP. Ceftaroline fosamil, the prodrug of ceftaroline, is a new extended-spectrum cephalosporin that exhibits time-dependant bactericidal activity against numerous Gram-negative and Gram-positive organisms, including methicillin-resistant Staphylococcus aureus and penicillin-resistant S. pneumoniae. Notable exceptions include Pseudomonas spp. and Gram-negative organisms that produce extended-spectrum β-lactamases or carbapenemases. Two large Phase III clinical trials (FOCUS 1 and 2) reported that ceftaroline fosamil was well tolerated, with a clinical cure rate of CAP that was noninferior to that with ceftriaxone in nonintensive care unit adult inpatients with moderately severe (Pneumonia Outcomes Research Team score of III or IV) community-acquired pneumonia.     

Safety and efficacy of sequential i.v. to p.o. moxifloxacin versus conventional combination therapies for the treatment of community-acquired pneumonia in patients requiring initial i.v. therapy

To compare the efficacy of sequential i.v. to p.o. moxifloxacin with ceftriaxone ± azithromycin ± metronidazole for the treatment of patients with community acquired pneumonia (CAP), a multi-centered, prospective, randomized, open label study was performed. CAP patients were randomized to moxifloxacin (400 mg/d—at least one i.v. dose) or ceftriaxone (at least one dose of 2 g i.v. q.d. followed by cefuroxime 500 mg p.o. b.i.d.) ± azithromycin, ± metronidazole (cephalosporin/macrolide control: CMC). The primary endpoint was clinical response at test-of-cure (TOC) visit. Bacteriological response at TOC was the secondary endpoint. Clinical cure was found in 83.3% (90/108) of moxifloxacin patients and 79.6% (90/113) of control patients. Microbiological responses were 81.8% (18/22) for moxifloxacin and 60.7% (17/28) for CMC patients. Drug-related adverse events occurred in 18.0% of moxifloxacin and 16% of CMC patients. It is concluded that i.v. to p.o. moxifloxacin is as effective as CMC for treatment of CAP and is a reliable alternative antimicrobial therapy.     

Levofloxacin for the treatment of community-acquired pneumonia

New respiratory fluoroquinolones (FQs), such as levofloxacin, offer many improved qualities over older agents, such as ciprofloxacin. These include retaining excellent Gram-negative bacilli activity, with improved Gram-positive activity. New FQ-like levofloxacin possesses greater bioavailabilty and a longer serum half-life compared with ciprofloxacin, allowing for once-daily dosing, which may improve patient adherence. The high bioavailability of levofloxacin allows for rapid step-down from intravenous administration to oral therapy, minimizing unnecessary hospitalization, which may decrease costs and improve patient quality of life. Levofloxacin has been evaluated for the treatment of community-acquired pneumonia (CAP) in numerous randomized clinical trials. Most published studies have used the 500 mg dose, although more recent studies have investigated the 750 mg dose once daily. These trials demonstrate that levofloxacin is effective and safe for the treatment of CAP, displaying relatively mild adverse effects that are more or less comparable with ciprofloxacin. Levofloxacin has much to offer in terms of bacterial eradication, including for resistant respiratory pathogens. However, ciprofloxacin-resistant organisms are becoming more prevalent so prudence must be exercised when prescribing this agent.     

A novel treatment option for MRSA pneumonia: ceftaroline fosamil-yielding new hope in the fight against a persistent infection

Methicillin-resistant Staphylococcus aureus (MRSA) hospital-acquired pneumonia (HAP) and healthcare-associated pneumonia (HCAP) patients treated with current antibiotic therapies have exhibited poor outcomes, increased hospital length of stay, and higher costs of care. The optimal management of these infections is undetermined; thus, it is critical to look at ways to improve outcomes in these patients. There is insufficient data on clinical efficacy in patients with MRSA HAP or HCAP infection treated with ceftaroline-fosamil. In a recent pilot study, nearly 90% of patients treated with ceftaroline-fosamil survived, despite the difficulties associated with administrating bactericidal antimicrobial therapy for this increasingly resistant pathogen. These data suggest a possible benefit in the use of ceftaroline-fosamil for MRSA pneumonia. Presently, we have identified cases over a two-year period treated with ceftaroline-fosamil, and will conduct a comparative analysis to controls (those treated with vancomycin and/or cefepime, and linezolid) to determine optimal therapeutic agents; these findings will have important implications for control of further spread of infection, recurrence, readmission, and mortality attributable to MRSA HAP and HCAP.     

Approaches to treatment of community-acquired pneumonia in the emergency department and the appropriate role of fluoroquinolones

The Emergency Department is a critical point of care for patients presenting with signs and symptoms of community-acquired pneumonia (CAP). The initial diagnosis, the decision to admit or discharge, the timing of initiating treatment, and appropriateness of the empirical therapy are key factors in successful management. Rising resistance rates to commonly used CAP antibiotics has complicated empirical treatment. Respiratory fluoroquinolones represent an important therapeutic option for patients with co-morbidities and risk factors for penicillin-, macrolide-, and multi-drug-resistant S. pneumoniae infections. Ensuring appropriate use is required to maintain their high level of effectiveness in key respiratory pathogens. Treatment guidelines from the Infectious Diseases Society of America, American Thoracic Society, and Centers for Disease Control and Prevention are available to assist emergency physicians in developing clinical pathways to ensure appropriate use of available therapies.     

Telavancin for the treatment of hospital-acquired pneumonia: findings from the ATTAIN studies

Treatment options for hospital-acquired pneumonia caused by Gram-positive organisms are far from ideal. The increase in vancomycin MICs among methicillin-resistant Staphylococcus aureus (MRSA) isolates, and the slow bactericidal action and poor lung penetration of vancomycin have driven the search for an alternative agent. Telavancin, a once-daily lipoglycopeptide, displays strong bactericidal activity against S. aureus. Two large Phase III randomized trials have recently compared intravenous telavancin (10mg/kg every 24?h) with vancomycin (1?g intravenously every 12?h) for 7–21 days for the treatment of hospital-acquired pneumonia caused by Gram positives. No significant differences were observed in the cure rates in the all-treated (n = 1503), the clinically evaluable (n = 654) and the microbiologically evaluable (n =480) populations. Telavancin performed better than vancomycin in patients with monomicrobial S. aureus pneumonia (84.2 vs 74.3%; 95% CI: 0.7–19.1), with MRSA (81.8 vs 74.1%; 95% CI: –3.5 to 19.3), and with strains having vancomycin MICs ≥1µg/ml (87.1 vs 74.3; 95% CI: 0.5–23). The rate of adverse events, including serious adverse events, was similar in both groups, with a slightly higher rate of serum creatinine increase in the telavancin-treated group. Based on these results, telavancin (already approved for this indication by the EMA) could certainly be added to the current treatment options, particularly in patients with MRSA pneumonia.     

Tigecycline for the treatment of patients with community-acquired pneumonia requiring hospitalization

Pneumonia, along with influenza, is the leading cause of mortality associated with infectious diseases in the USA. Tigecycline is a novel antimicrobial agent that is active against a broad spectrum of pathogens. Our objective is to review the literature about the efficacy of tigecycline in community-acquired pneumonia (CAP). Data from various sources, including Pubmed, the European Medicines Agency (EMEA) and the US FDA were appraised. Tigecycline was found to be noninferior compared with levofloxacin for the treatment of patients with bacterial CAP requiring hospitalization. Recently, the drug was approved for the treatment of these patients by the FDA, but owing to some concerns, its application in the EMEA has been withdrawn. In addition, in a recent study concerns were expressed about the efficacy of tigecycline in the lungs using the current dosage. More data are needed about the pharmacokinetics of tigecycline in the lungs and its efficacy in severe CAP.     

谵妄与老年社区获得性肺炎患者住院期间死亡的相关分析

目的分析老年社区获得性肺炎患者谵妄的发生率及谵妄与老年社区获得性肺炎（CAP）患者住院期间死亡的关系。方法收集在本院接受治疗的老年CAP患者126例,分成死亡组（16例）和生存组（110例）。记录所有患者年龄、性别、体质量指数、并存疾病、谵妄发生、CURB-65评分、肺炎严重指数（PSI）评分、急性病生理学和长期健康评价（APACHE）Ⅱ评分等资料,采用单因素和多因素分析谵妄与住院期间死亡的关系,采用受试者工作特征曲线分析谵妄对住院期间死亡的预测价值。结果本组老年CAP患者发生谵妄29例（23.0%）,谵妄患者住院期间病死率为31.0%（9/29）,谵妄使老年CAP患者住院期间病死率增加5.785倍。单因素分析显示,与生存组相比,住院期间死亡组患者年龄更大、谵妄发生率更高、CURB-65评分、PSI评分及APACHEⅡ评分均显著升高（t=2.081,χ2=11.425,t=5.074、4.706、4.431,P均〈0.05）。多因素Logistic回归分析显示,谵妄、CURB-65评分、PSI评分及APACHEⅡ评分是老年CAP患者住院期间死亡的独立危险因素（P均〈0.05）。受试者工作特征曲线分析显示,谵妄预测住院期间死亡有中等曲线下面积及灵敏度和特异度,且与CURB-65评分、PSI评分及APACHEⅡ评分的曲线下面积比较,差异均无统计学意义（P均〉0.05）。结论老年CAP患者谵妄发生率较高,谵妄是老年CAP患者住院期间死亡的独立危险因素,加强对谵妄的诊治可能降低CAP患者的病死率。     

A comparative study of meropenem and ceftazidime in the treatment of patients hospitalized with community-acquired pneumonia

This multicenter, open-label, randomized clinical trial compared the efficacy and tolerability of intravenous (IV) meropenem 0.5 g every 8 hours (n = 147) and IV ceftazidime 1 g every 8 hours (n = 148) as empiric monotherapy for 295 patients hospitalized with community-acquired pneumonia. Seventy-four meropenem recipients and 81 ceftazidime recipients with pneumonia were assessable both clinically and bacteriologically. In these patients, no statistically significant differences were reported in the satisfactory clinical (95% with meropenem vs 90% with ceftazidime) or bacteriologic (95% with meropenem vs 93% with ceftazidime) response rates with the two agents at the end of treatment. High satisfactory clinical (95% with meropenem vs 92% with ceftazidime) and bacteriologic (97% with meropenem vs 89% with ceftazidime) response rates were maintained at follow-up (2 to 4 weeks later). In 90 patients who were clinically assessable but bacteriologically unassessable (no pretreatment pathogen isolated), both agents produced a satisfactory clinical response rate of 87% at the end of therapy. Streptococcus pneumoniae was the most frequently isolated pretreatment pathogen (28%), but nosocomial-type pathogens such as Escherichia coli (5%), Pseudomonas aeruginosa (11%), and Klebsiella pneumoniae (6%) were also frequently isolated. Both medications were well tolerated, and the types of treatment-related adverse events were similar in the two treatment groups. These findings indicate that meropenem 0.5 g every 8 hours is a useful option for the empiric treatment of patients hospitalized with community-acquired pneumonia.     

IV-to-oral switch therapy for community-acquired pneumonia requiring hospitalization: focus on gatifloxacin

The majority of the 1.1 million patients hospitalized for community-acquired pneumonia (CAP) in the United States begin therapy with an intravenous antibiotic. A switch to oral therapy as soon as patients are clinically stable reduces the length of hospitalization and associated costs. Fluoroquinolones are appropriate candidates for switch therapy. Gatifloxacin is an excellent choice when a fluoroquinolone is being considered for sequential switch therapy in the treatment of CAP requiring hospitalization.     

Levofloxacin in the treatment of community-acquired pneumonia

Levofloxacin is a fluoroquinolone that has a broad spectrum of activity against several causative bacterial pathogens of community-acquired pneumonia (CAP). The efficacy and tolerability of levofloxacin 500 mg once daily for 10 days in patients with CAP are well established. Furthermore, a high-dose (750 mg), short-course (5 days) of once-daily levofloxacin has been approved for use in the USA in the treatment of CAP, acute bacterial sinusitis, acute pyelonephritis and complicated urinary tract infections. Levofloxacin can be used as a monotherapy in patients with CAP, however, levofloxacin combination therapy with anti-pseudomonal β-lactam (or aminoglycoside) should be considered if Pseudomonas aeruginosa is the causative pathogen of the respiratory infection. The high-dose, short-course levofloxacin regimen maximizes its concentration-dependent antibacterial activity, decreases the potential for drug resistance and has better patient compliance. Oral levofloxacin is rapidly absorbed and is bioequivalent to the intravenous formulation and the patients can switch between these formulations, which results in more options with respect to the therapeutic regimens. Furthermore, levofloxacin is generally well tolerated, has good tissue penetration and adequate concentrations can be maintained at the site of infections.     

血清降钙素原动态监测在肺炎严重程度评估和预后判断中的应用价值

目的探讨社区获得性肺炎（CAP）住院患者血清降钙素原（PCT）动态监测在评估肺炎严重程度和预后判断中的应用价值。方法对某社区的100倒CAP患者的临床资料进行回顾性分析,并于入院次日清晨抽取外周静脉血,采用酶联免疫吸附试验（ELLSA）对患者血清中的PCT水平进行测定、分析,将其按照严重程度分为三组,即普通CAP组（49例）、重症cAP组（39例）及死亡CAP组（12例）,比较三组基线资料、血PCT浓度及简化肺炎预后评分系统（PORT）分层与PCT水平的相关性。结果（1）三组患者中,平均年龄、简化PORT评分、平均住院时间、静脉抗菌药物使用时间、住院费用等方面的差异均具有统计学意义（P〈0．05）;（2）三组血清PCT水平从低到高依次为：普通cAP组、重症cAP组、死亡CAP组,且两两比较差异具有统计学意义（P〈o．05）;（3）血清PCT水平与PORT分层的相关系数为0．929（Pd0．05）。结论CAP住院患者血清PCT动态监测在评估肺炎严重程度和预后判断中具有较大的价值,能够提高患者的临床诊断准确度,有助于及时地采取有效的治疗措施。     

A new prediction model for assessing the clinical outcomes of ICU patients with community-acquired pneumonia: a decision tree analysis

Purpose: We aimed to develop a new scoring index based on decision-tree analysis to predict clinical outcomes of patients with community-acquired pneumonia (CAP) admitted to the intensive care unit (ICU).

Methods: Data of 3519 ICU patients with CAP were obtained from the Medical Information Mart for Intensive Care III (MIMIC III) 2001–2012 database and analysed between 30-d survivors and non-survivors. Accuracy, sensitivity, and specificity of the new decision tree model were compared with those of CURB-65 and SOAR.

Results: The newly developed classification and regression tree (CART) model identified coexisting illnesses as the most important single discriminating factor between survivors and non-survivors. The CART model area under the curve (AUC) 0.661 was superior to that of CURB-65 (0.609) and SOAR (0.589). CART sensitivity was 73.4%, and specificity 49.0%. CURB-65 and SOAR sensitivity for predicting 30-d mortality were 74.5 and 80.7%, and specificity was 42.3 and 33.9%, respectively. After smoothing, the CART model had higher sensitivity and specificity than both CURB-65 and SOAR.

Conclusions: The new CART prediction model has higher specificity and better receiver operating characteristics (ROC) curves than CURB-65 and SOAR score indices although its accuracy and sensitivity are only moderately better than the other systems.

• Key messages

• The new CART prediction model has higher specificity and better ROC curves than CURB-65 and SOAR score indices.

• However, accuracy and sensitivity of the new CART prediction model are only moderately better than the other systems in predicting 30-day mortality in CAP patients.

     

老年重症肺炎的治疗和预后危险因素分析

目的探讨老年重症肺炎病死率的危险因素，以提高临床的救治率。方法参照2001年美国胸科学会（ATS）指南对重症肺炎的诊断标准，分析54例重症肺炎患者的临床资料，其中经验性抗菌治疗按指南推荐方案治疗组36例，未按指南推荐方案治疗组18例。结果54例重症肺炎病死率为66．67％（36／54），死亡患者的平均年龄为（79±4）岁，高于生存者（70±5）岁的平均年龄，P〈0．05。按指南推荐方案治疗组和未按指南推荐方案治疗组的病死率分别为55．56％（20／36）和88．89％（16／18）；36例并有1～2个脏器功能衰竭和18例有三个以上脏器功能衰竭患者的病死率分别为55．56％（20／36）和88．89％（16／18），P〈0．05。患有一种以上的基础疾病96．30％（52／54），免疫功能低下70．37％（38／54），血浆白蛋白降低77．78％（42／54），P〈0．01。结论高龄、多脏器功能衰竭、伴有多种基础疾病、免疫功能低下及血浆白蛋白降低等是重症肺炎病死率的主要影响因素，选择按指南推荐方案治疗可降低重症肺炎病死率。     

血清25-羟基维生素D检测在儿童社区获得性肺炎中的应用及意义

目的探讨儿童社区获得性肺炎(CAP)患儿血清25-羟基维生素D水平及临床意义。方法采用电化学发光法和免疫透射比浊法分别测定66例CAP患儿和52名健康体检者(正常对照组)血清25-羟基维生素D和C反应蛋白(CRP)水平,并根据儿童CAP病情的轻重分为轻症组和重症组。结果儿童CAP组血清25-羟基维生素D水平[(27.05±10.93)μg/L]明显低于正常对照组[(32.77±9.78)μg/L](P0.01),而CRP水平[(11.77±5.98)mg/L]则高于正常对照组[(4.56±2.48)mg/L](P0.01)。同时,重症组血清25-羟基维生素D水平明显低于轻症组(P0.01),而平均年龄则大于轻症组(P0.01);CRP水平在两组之间无明显差异(P0.05)。结论血清25-羟基维生素D的缺乏可能是儿童CAP的潜在病因,在判断疾病的轻重上也有一定的意义。     

Assessment of ceftaroline fosamil in the treatment of community-acquired bacterial pneumonia due to Streptococcus pneumoniae: insights from two randomized trials

Ceftaroline fosamil resulted in higher cure rates than ceftriaxone in patients with community-acquired bacterial pneumonia in 2 randomized trials (FOCUS 1 and FOCUS 2). The present analysis examines the subgroup of patients with Streptococcus pneumoniae infection to determine whether the apparent difference in cure rates persists after adjusting for potential covariates. We retrospectively pooled subjects with S. pneumoniae isolated at baseline in the original studies and employed logistic regression to evaluate the independent relationship between clinical cure and treatment with ceftaroline. Covariates evaluated included demographics, severity of illness, bacteremia, and pathogen characteristics. The final cohort included 139 subjects (69 ceftaroline, 70 ceftriaxone). Unadjusted cure rates were 85.5% and 68.6% (P = 0.009) in the ceftaroline and ceftriaxone groups, respectively. After logistic regression, ceftaroline remained associated with higher cure rates. Our findings indicate that ceftaroline may result in improved outcomes of S. pneumoniae pneumonia. Formal clinical trials are warranted to confirm this hypothesis.     

rs1840680 single nucleotide polymorphism in Pentraxin 3: a potential protective biomarker of severe community-acquired pneumonia

ObjectiveSingle nucleotide polymorphisms (SNPs) of pentraxin 3 (PTX3) are associated with various outcomes of lung infections. This study aimed to analyze the relationship between PTX3 polymorphisms and the severity of community-acquired pneumonia (CAP).MethodsThis is a retrospective case-control study comprising 43 patients with severe CAP (SCAP) and 97 patients with non-severe CAP. Three SNPs in the PTX3 gene (rs2305619, rs3816527, and rs1840680) from peripheral blood samples were genotyped by real-time polymerase chain reaction. The association between each SNP and the CAP severity was analyzed by logistic regression analysis.ResultsWe found that the rs1840680 polymorphism was significantly associated with CAP clinical severity. However, no such association was observed for the genotypes and allele frequencies of rs2305619 or rs3816527. The PTX3 rs1840680 AG genotype was an independent factor for a lower risk of SCAP after multivariate logistic regression analysis. Male sex and coronary heart disease were associated with an increased risk of SCAP.ConclusionsThe PTX3 rs1840680 AG genotype was found to be associated with a lower risk of SCAP, and may serve as a potential protective biomarker to help clinical judgment and management.     

Early evolution of arterial oxygenation in severe community-acquired pneumonia: a prospective observational study

PURPOSE: Acute respiratory failure requiring mechanical ventilation in severe community-acquired pneumonia has been shown to be a significant negative prognostic factor. We analyzed the early evolution of the Pao(2)/Fio(2) ratio and evaluated its clinical value as an outcome predictor. MATERIALS AND METHODS: This is a prospective study conducted in a tertiary referral hospital. In 62 adult patients requiring early mechanical ventilation due to severe community-acquired pneumonia, we measured serial changes in Pao(2)/Fio(2) ratio and other clinical variables within the first 48 hours of mechanical ventilation and compared the difference between survivors and nonsurvivors. RESULTS: The initial Pao(2)/Fio(2) ratio was lower in nonsurvivors (n = 27) than in survivors (n = 35) (158.0 +/- 55.8 vs 117.9 +/- 50.6, P = .025). Over the next 48 hours, the ratio increased significantly in survivors but not in nonsurvivors (analysis of variance, P < .001). An increase in Pao(2)/Fio(2) ratio greater than 56 mm Hg had a sensitivity of 75% and a specificity of 81% of survival. A definite causative pathogen was identified in 36 patients (58%) and the 3 most commonly isolated pathogens were Streptococcus pneumoniae, Staphylococcus aureus, and Klebsiella pneumoniae. Ten patients received inadequate initial empirical antimicrobial therapy, in which the Pao(2)/Fio(2) ratio change was significantly less than those who were adequately treated (analysis of variance, P < .001). Mortality was much higher (86% [6/7]) in patients who received inadequate antibiotics and where Pao(2)/Fio(2) ratio change was less than 56 mm Hg. On multivariate analysis, trend changes in Pao(2)/Fio(2) ratio over 48 hours, shock, and Acute Physiology and Chronic Health Evaluation II score were documented to be independent predictors of mortality. CONCLUSIONS: A progressive improvement of Pao(2)/Fio(2) ratio during the first 48 hours of mechanical ventilation indicates favorable outcome. Serial measurement of this ratio should be considered in decision making for therapeutic strategy.