Ceftaroline vs Cerftiaxone plus Vancomycin P903-24

Overview

Status: Not yet recruiting
Keywords: Ceftaroline , Ceftriaxone , Vancomycin , Pneumonia , CABP
IRB Number: 00062165
Specialty: Pediatric Infectious Diseases
Sub Specialties:

Brief Summary

6.0 STUDY OBJECTIVES

6.1 PRIMARY
Evaluate the safety and tolerability of ceftaroline versus ceftriaxone plus vancomycin in pediatric subjects ages 2 months to < 18 years with complicated CABP.
 
6.2 SECONDARY
• Evaluate the efficacy of ceftaroline versus ceftriaxone plus vancomycin in pediatric subjects with complicated CABP at high risk of infection due to MRSA
• Evaluate the pharmacokinetics of ceftaroline in pediatric subjects ages 2 months to < 18 years with complicated CABP

Detailed Description

Community-acquired bacterial pneumonia (CABP) is among the most common serious infections affecting adult and pediatric patients and a major cause of morbidity and mortality worldwide. The highest incidence rates occur at the extreme periods of life, in the very young and the very old. In a community-based study in Finland conducted in 1981 through 1982, radiologically-confirmed pneumonia had an incidence of 36 cases/1,000 population for children aged < 5 years and 16.2 cases/1,000 population for those 5 to 14 years of age (Farha and Thomson, 2005). The risk for severe childhood CABP is significantly increased for children < 5 years of age (Antonelli et al, 2009). In Europe, more than 2.5 million cases of childhood pneumonia occur annually and account for approximately 50% of hospital admissions for pediatric patients. Pneumonia is responsible for an estimated 1.9 million deaths worldwide in children < 5 years of age (Ranganathan and Sonnappa, 2009). In children > 3 weeks old, Streptococcus pneumoniae is a leading cause of CABP (Dennehy, 2010). Pediatric patients are particularly predisposed to antimicrobial resistance, with the highest prevalence of penicillin-nonsusceptible S. pneumoniae (PNSSP) occurring in pediatric patients < 2 years of age (Sinaniotis and Sinaniotis, 2005). Additional risk factors for antimicrobial resistance include recent hospitalization, day care facility attendance, and prior antimicrobial therapy. Even with the introduction of the heptavalent pneumococcal conjugate vaccine (PCV7), which contains serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F, as an approach to reduce S. pneumoniae disease and resistance, the burden of PNSSP and multidrug-resistant S. pneumoniae (MDRSP) among vaccine and nonvaccine serotypes remains a concern (Elliott, 2008). Although PCV7 has substantially decreased the rate of pneumococcal infections in children, the prevalence of invasive pneumococcal disease has increased in serotypes (susceptible and nonsusceptible) not covered by the vaccine. After the introduction of the PCV7, serotype 19A, with resistance to all FDA-approved and 8 non-FDA-approved antimicrobials, emerged as a serious contributor of invasive pneumococcal disease in the United States. The emergence of pneumococcal disease caused by non-PCV7 serotypes, particularly multi-resistant serotype 19A, has also been observed outside of the United States (Picazo, 2009). Since the introduction of PCV7, the most common invasive pneumococcal isolates in Belgium, France, Germany, Greece, Norway, Portugal, Spain, and the United Kingdom were serotypes 1, 19A, 3, 6A, and 7F (Isaacman et al, 2009). A higher prevalence of non-PCV7 serotypes, such as 1 and 5, has been observed in Western Europe (Jefferson et al, 2006). Multidrug-resistant 19A strains with minimum inhibitoryconcentrations (MICs) to ceftriaxone of 8.0 mg/L have also been reported (Woodhead, et al 2005). The recently developed pneumococcal 13-valent conjugate vaccine (PCV13), which contains PCV7 strains plus serotypes 1, 3, 5, 6A, 7F, and 19A, was licensed in Dec 2009 by the Committee for Medicinal Products for Human Use of the European Medicines Agency and was approved in Feb 2010 by the FDA for use in children 6 weeks through 5 years for active immunization for the prevention of invasive disease caused by S. pneumonia serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F (Electronic Medicines Compendium, 2011; Prevnar 13 package insert, 2011). In addition, new strains continue to emerge. Neither serotype 33, which has been associated with erythromycin resistance, or a newly identified serotype, 6C, which, although epidemiological data is limited, is known to be genetically diverse and often resistant to antibiotic therapy, are targeted by PCV13. Nunes et al (2009) reported data from Portugal that indicate the prevalence of serotype 6C from 1999 to 2007 ranged from 0.2% to 5.8%, with the highest prevalence occurring in 2007. Another important pathogen, Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), has emerged in CABP. In children, the incidence of community-acquired pneumonia (CAP) due to S. aureus is increasing. In one study at the Texas Children’s Hospital from August 2001 to April 2009 (Carrillo-Marquez et al, 2011), 117 children aged 0.05 to 20.9 years were identified who had pneumonia due to S aureus, and the rate of such pneumonia per 10,000 admissions increased from 4.81 hospitalizations in Year 1 to 9.75 in Year 7 (p = 0.04). Furthermore, community-acquired methicillin-resistant S. aureus (CA-MRSA) has increasingly been recognized as an important pathogen in CABP. In children and adults, CA-MRSA has been associated with a severe, necrotizing form of CAP associated with Panton-Valentine leukocidin (PVL) production and has an overall mortality rate of 56%; refractory shock, airway bleeding, and leucopenia have been associated with fatal outcomes in these patients (Gillet et al, 2007). The incidence of severe MRSA CAP appears to be rising, with increasing reports during recent influenza seasons (CDC, 2007; CDC, 2009). Pneumonia due to CA-MRSA in children is often “complicated” CABP, in that many cases feature complications as empyema, lung abscess, and the need for surgical drainage (Carrillo-Marquez et al, 2011). Such cases may be indistinguishable from those caused by more common typical pathogens, such as methicillin-susceptible S. aureus (MSSA) (Gonzalez et al, 2005) or S. pneumoniae (Talan et al, 2010). Treatment options for CA-MRSA infections are limited. Vancomycin concentrates poorly in the alveoli and has been found to be inferior to β-lactams in severe MSSA infections (Kim et al, 2008). Other alternatives for treating CA-MRSA include linezolid (associated with myelosuppression and cases of lactic acidosis, peripheral neuropathy, and optic neuritis were also reported) and this underscores the need for new antibiotics for the treatment of severe CABP due to CA-MRSA. Toxicities and substantial treatment-limiting adverse reactions are of concern with use of the currently available antibiotic agents for CABP. For example, multiple approved antibiotics for CABP have label safety warnings, including carbapenems (seizures), macrolides (severe vomiting, diarrhea, hepatic and fetal toxicity), fluoroquinolones (tendinopathy and tendon rupture, QT prolongation, hematological toxicities, central nervous system effects, peripheral neuropathy), linezolid (associated with myelosuppression and cases of lactic acidosis, peripheral neuropathy, and optic neuritis were also reported), and cephalosporins (rarely seizures, hemolytic anemia, renal toxicities, and liver abnormalities) that make these agents unsuitable therapeutic agents for certain patients. The following factors support the use of ceftaroline in a clinical trial to treat CABP in pediatric subjects ≥ 2 months of age: • Unlike most other β-lactams, ceftaroline has a high affinity for the penicillin-binding protein 2x (PBP2x) in MDRSP, which contributes to ceftaroline’s favorable activity against penicillin-resistant S. pneumoniae (PRSP) • Ceftaroline retains potent in vitro activity against common pathogens (including resistant phenotypes) associated with respiratory infections. Ceftaroline is active not only against S. pneumoniae strains that are resistant to penicillin including serotypes such as 19A and 6C, but it is active against multidrug resistant strains (strains resistant to two or more of the following classes of antibiotics: penicillins, macrolides, tetracycline, fluoroquinolones, chloramphenicol, trimethoprim sulfamethoxazole, and second generation cephalosporins). Ceftaroline also showed activity against highly cephalosporin-resistant clinical isolates of S. pneumoniae (Jacobs et al, 2010). • Ceftaroline offers a broad spectrum of activity against common gram-positive and gram-negative pathogens including potent in vitro activity against MDRSP and MRSA due to its high affinity for PBP2a and PBP2x • The clinical cure rates at Test-of-Cure (TOC) in two Phase 3 clinical trials in adult subjects with CABP were 86.6% and 82.3% for ceftaroline, which compared favorably with the ceftriaxone rates of 78.2% and 77.1%. In addition, the clinical cure rates for the most prevalent pathogen, S. pneumoniae, were 85.7% for ceftaroline and 69.5% for ceftriaxone in these integrated CABP trials. • Ceftaroline was well-tolerated in adult clinical trials and had a safety profile consistent with available marketed cephalosporins, a class of antibiotics with a long history of clinical use • On 29 Oct 2010 the FDA approved ceftaroline fosamil for the treatment of CABP as well as for the treatment of acute bacterial skin and skin structure infection in adults Therefore, ceftaroline has the potential to be a valuable agent for use in pediatric medicine as a well-tolerated and effective antibiotic that has enhanced gram-positive coverage, including activity against emerging difficult to treat pathogens such as S. pneumoniae serotype 19A and CA-MRSA in an environment with currently limited therapeutic options. This is particularly important since there are complexities in diagnosing the etiologic agent of CABP and prompt initiation of empirical therapy is desired.

Principal Investigator: Michael Spigarelli
Department: Pediatric Administration
Co Investigator: Kwabena Ampofo

Contact Information

Name:Rachel Brodis
Phone: 801-585-9072
Email: rachel.douglas@hsc.utah.edu

Inclusion Criteria

1. Informed consent in writing from parent(s) or other legally acceptable representative(s) and informed assent from subject (if age appropriate according to local requirements)

2. Male or female 2 months to < 18 years of age

3. Presence of CABP warranting 3 days of initial hospitalization and a minimum of 3 days of IV antibacterial therapy and a minimum of 5 days but no more than 21 days total of study therapy (IV and PO combined)
4. Presence of CABP meeting each of the following criteria:
     I. Fever (temperature > 38.0°C) or hypothermia (temperature < 35.0°C).  Temperature should not be measured by the axillary method.
     II. New infiltrate(s) compatible with bacterial pneumonia, including a new alveolar/lobar infiltrate or consolidation (based on imaging results or diagnostic testing)
     III. Confirmed presence of at least 1 indicator of complicated CABP or staphylococcal pneumonia, defined as:
          ○ Empyema defined as the presence of pus and fluid from infected tissue collected in the pleural space as confirmed via thoracentesis
          ○ Pulmonary abscess defined as a collection of pus in the lung
          ○ Necrotizing pneumonia defined as a consolidative pneumonia that has areas of nonenhancement on contrast-enhanced computed tomography (CT) but no air-fluid level or rim enhancement or development of a pneumatocele after the pneumonia
          ○ Pneumatocele defined as a thin-walled, air-containing cyst of the lungs
          ○ Pleural effusion needing chest tube drainage, but not considered an empyema
          ○ Gram positive cocci in clusters on Gram stain from a respiratory specimen (eg, sputum, pleural fluid, deep bronchial [eg, bronchoalveolar lavage], deep tracheal)
         ○ Requirement for positive pressure assisted ventilation
         ○ Previous influenza-like illness (defined as temperature > 38.0°C plus cough or sore throat in the absence of a known cause other than influenza) or documented influenza infection (eg, by culture or molecular testing) within 28 days of enrollment
         ○ Severe CABP, defined as requirement for treatment in an intensive care unit
     IV. Acute onset or worsening within the previous 5 days before randomization of at least 2 of the following clinical signs or symptoms:
○ Cough
○ Tachypnea defined as:
       - 2 months to < 12 months: ≥ 50 breaths/min
       - 12 months to < 5 years: ≥ 40 breaths/min
       - ≥ 5 years: ≥ 20 breaths/min
○ Dyspnea
○ Grunting
○ Sputum production
○ Chest pain
○ Cyanosis
○ Evidence of pneumonia with parenchymal consolidation (eg, dullness on percussion, diminished breath sounds, egophony, bronchial breath sounds, rales or crackles)
○ Increased work of breathing (eg, nasal flaring, chest wall retractions)
     V. Presence of at least 1 of the following:
○ Organism consistent with a typical respiratory pathogen identified or isolated from a respiratory or blood culture
○ Leukocytosis (> 15,000 white blood cells [WBC]/mm3)
○ > 15% immature neutrophils (bands) regardless of total peripheral WBC
○ Leucopenia (< 4500 WBC/mm3) likely due to the bacterial infection
○ Hypoxemia (oxygen saturation < 92% on room air)
5. Female subjects who have reached menarche must have a negative urine pregnancy test
6. Female subjects who have reached menarche and are sexually active must be willing to practice sexual abstinence or dual methods of birth control (eg, condom or diaphragm with spermicidal foam or gel) during treatment and for at least 28 days after the last dose of any study drug (IV or PO)
7. Sufficient IV access to receive medication

 

Exclusion Criteria

1. Documented history of any hypersensitivity or allergic reaction to vancomycin or any β-lactam antimicrobial

2. Confirmed or, based upon the epidemiological context, suspected infection with a pathogen known to be resistant to IV study drugs (eg, Pseudomonas aeruginosa) or known infection at baseline with a sole atypical organism (eg, Mycoplasma pneumoniae, Chlamydophila pneumoniae, Chlamydia trachomatis, Legionella pneumophila)
3. Confirmed or suspected respiratory tract infection attributable to sources other than community-acquired bacterial pathogens (eg, ventilator-associated pneumonia; hospital-acquired pneumonia; visible/gross aspiration pneumonia; suspected sole viral [eg, respiratory syncytial virus], fungal, Mycobacterium tuberculosis infection of the lung); chronic lung disease or neurologic disease preventing normal clearance of secretions
4. Non-infectious causes of pulmonary infiltrates (eg, cystic fibrosis, chemical pneumonitis from aspiration, hypersensitivity pneumonia) on chest radiography 
5. More than 24 hours of any potentially effective systemic antibacterial therapy for CABP within 96 hours before randomization.  Exceptions: a) Microbiological or clinical treatment failure with a nonstudy antibacterial therapy that was administered for at least 48 hours. Failure must be confirmed by either a microbiological laboratory report or documented worsening clinical signs or symptoms; b) Low-dose tetracycline derivatives for acne (eg, doxycycline 50 mg q12h)
6. Requirement for any potentially effective concomitant systemic antibacterial therapy
7. History of seizures, excluding febrile seizure of childhood
8. CrCl < 50 mL/min/1.73 m2 as calculated using the updated Schwartz “bedside” formula:
CrCl (mL/min/1.73 m2) = 0.413 × height (length) (cm)/serum creatinine (mg/dL)
9. Clinical signs or suspicion of bacterial meningitis
10. Evidence of significant hepatic, hematologic, or immunocompromising condition (any of the following):
○ Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5 times upper limit of normal (× ULN)
○ Total bilirubin > 2 × ULN
○ Known acute viral hepatitis
○ Neutropenia (< 500 neutrophils/mm3)
○ Thrombocytopenia (< 60,000 platelets/mm3)
○ If human immunodeficiency virus (HIV)-positive, has either a CD4 count < 250 cells/mm3 at the last measurement or a history of an AIDS-defining illness
○ Bone marrow ablative therapy, including bone marrow transplantation, within the last 12 months
○ Bone marrow or solid organ recipients who have had an episode of graft versus host disease or acute rejection episode, respectively, within the last 6 months
○ Severe combined immunodeficiency disorder (SCID)
11. Evidence of immediately life-threatening disease (with the exception of CABP), progressively fatal disease, or life expectancy of 3 months or less
12. Females who are currently pregnant or breastfeeding
13. Participation in any study involving administration of an investigational agent or device within 30 days before randomization or previously participated in the current study or in another study of ceftaroline fosamil (in which an active agent was taken or received)
14. Unable or unwilling to adhere to the study-specified procedures and restrictions
15. Any condition that would make the subject, in the opinion of the Investigator, unsuitable for the study (eg, would place a subject at risk or compromise the quality of the data)