Ceftaroline vs Ceftriaxone P903-31

Overview

Status: Not yet recruiting
Keywords: Ceftaroline , Ceftriaxone , Pneumonia , CABP
IRB Number: 00062657
Specialty: Pediatric Infectious Diseases
Sub Specialties:

Brief Summary

7.1.1 Primary Outcome Measures

Safety evaluations will be conducted in the Safety Population and assessments will include:

Adverse events: AEs, SAEs, deaths, and discontinuations due to AEs will be evaluated. Cephalosporin class effects and additional AEs (including, but not limited to, seizures, Clostridium difficile-associated diarrhea, allergic reactions, hemolytic anemia, hepatic abnormalities, and changes in renal function) will be closely monitored.

Clinical: vital signs (pulse, blood pressure, respiratory rate, oxygen saturation, and temperature)

Laboratory: complete blood count with differential, direct Coombs test, and chemistry panel

7.1.2 Secondary Outcome Measures

7.1.2.1 Efficacy Outcome Measures

Clinical response at Study Day 4 by subject and by baseline pathogen in the Modified Intent-to-Treat (MITT) and the Microbiological Modified Intent-to-Treat (mMITT) Populations

Clinical stability at Study Day 4 by subject and by baseline pathogen in the MITT and mMITT Populations

Clinical outcome at End-of-Intravenous Study Drug (EOIV), EOT, and TOC in the MITT and CE Populations

 

Clinical and microbiological outcomes by subject and by baseline pathogen at TOC in the mMITT and Microbiologically Evaluable (ME) Populations

Clinical relapse at Late Follow-up (LFU) in the MITT Population

Emergent infections in the mMITT Population

7.1.2.2 Pharmacokinetic Outcome Measures

Concentrations of ceftaroline fosamil, ceftaroline, and ceftaroline M-1 in plasma

If available, concentrations of ceftaroline fosamil, ceftaroline, and ceftaroline M-1 in cerebrospinal fluid (CSF)

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 neumococcal 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). Higher prevalences of non-PCV7 serotypes, such as 1 and 5, have been observed in Western Europe (Jefferson et al, 2006). Multidrug-resistant 19A strains with minimum inhibitory concentrations (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). 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. Ceftaroline, with its activity against S. pneumoniae (including multidrug resistant strains), has the potential to provide a valuable therapeutic option in the treatment of childhood CABP. 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 proteins PBP2x and PBP2a, which contribute to ceftaroline’s favorable activity against S. pneumoniae including penicillin-resistant S. pneumoniae and MRSA, respectively. • 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). • 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 community-acquired methicillin-resistant S. aureus (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

Subjects are required to meet the following 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 requiring hospitalization and IV antibacterial therapy

4. Presence of CABP meeting each of the following criteria:

I. Fever (temperature > 38.0°C) or hypothermia (temperature < 35.0°C). Note that 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. 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 (World Health Organization, 2011):

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)

IV. 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

Leukopenia (< 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

Subjects must NOT meet any of the following exclusion criteria:

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

2. Confirmed or suspected infection with a pathogen known to be resistant to ceftriaxone (eg, Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus [MRSA]) or known infection at baseline with a sole atypical organism (eg, Mycoplasma pneumoniae, Chlamydophila pneumoniae, Chlamydia trachomatis, Legionella pneumophila). Epidemiological clues to potential MRSA infection include necrotizing pneumonia, existence of an ongoing local MRSA infection outbreak, known skin colonization with MRSA, recent invasive MRSA infection, and recent influenza. Subjects with risk factors for MRSA infection who have predominance of gram-positive cocci in clusters on sputum Gram stain should also be excluded.

3. Confirmed or suspected respiratory tract infection attributable to sources other than community-acquired bacterial pathogens (eg, ventilator-associated pneumonia; hospital-acquired pneumonia [occurring 48 hours or more after admission, which was not incubating at the time of admission (Niederman, 1996; Tablan et al, 2004)]; 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 an antibiotic other than IV study drugs 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 derivative for acne (eg, doxycycline 50 mg q12h)

6. Requirement for any potentially effective concomitant systemic antibacterial therapy

7. Requirement for more than 10 days of systemic corticosteroid therapy (any dose)

8. History of seizures, excluding febrile seizure of childhood

9. Creatinine clearance < 50 mL/min/1.73 m2 as calculated using the updated Schwartz “bedside” formula (Schwartz et al, 2009): CrCl (mL/min/1.73 m2) = [0.413 × height (length) (cm)] / serum creatinine (mg/dL)

10. Clinical signs or suspicion of bacterial meningitis

11. Evidence of significant hepatic, hematologic, or immunocompromising condition (any of the following):

Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 times the upper limit of normal (× ULN) or total bilirubin level > 2 × ULN

Known acute viral hepatitis

Neutropenia (< 500 neutrophils/mm3)

Thrombocytopenia (< 60,000 platelets/mm3)

If human immunodeficiency virus (HIV)-positive, has CD4 count

< 250 cells/mm3 at the last measurement or history of 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)

 

12. Evidence of immediately life-threatening disease, progressively fatal disease, or life expectancy of 3 months or less

13. Females who are currently pregnant or breastfeeding

14. 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)

15. Unable or unwilling to adhere to the study-specified procedures and restrictions

16. Any condition (eg, septic shock, acute hemodynamic instability non-responsive to pressor support) 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)