Ceft-to-Ceft Study: Real-Life Experience with Ceftaroline and Ceftobiprole in Treatment of the Principal Infectious Syndromes in a Spanish Multicenter Hospital Cohort
by
Daniel Arnés García
1, 
Inés Pitto-Robles
1,
Jorge Calderón Parra
2,
Marina Calvo Salvador
3,
Carmen Herrero Rodríguez
4,
Laura Gisbert
5 and
Carmen Hidalgo-Tenorio
6,* 1
Servicio de Medicina Interna, Hospital Universitario Virgen de las Nieves, 18014 Granada, Spain
2
Unidad Enfermedades Infecciosas, Hospital Puerta de Hierro de Majadahonda, 28222 Madrid, Spain
3
Servicio de Farmacia, Hospital Puerta de Hierro de Majadahonda, 28222 Madrid, Spain
4
Unidad de Enfermedades Infecciosas y Microbiología, Complejo Hospitalario de Jaén, 23007 Jaén, Spain
5
Unidad de Enfermedades Infecciosas, Hospital Universitario Mútua de Terrassa, 08221 Barcelona, Spain
6
Unidad de Enfermedades Infecciosas, Hospital Universitario Virgen de las Nieves, Instituto de Investigación Biosanitario de Granada (IBS-Granada), 18014 Granada, Spain
*
Author to whom correspondence should be addressed.
Antibiotics 2023, 12(12), 1692; https://doi.org/10.3390/antibiotics12121692
Submission received: 19 October 2023
/
Revised: 17 November 2023
/
Accepted: 30 November 2023
/
Published: 2 December 2023
Abstract
:Background: To compare the real-life effectiveness and safety of ceftaroline fosamil (ceftaroline-F) and ceftobiprole medocaril (ceftobiprole-M) for infections in hospitalized patients. Methods: This comparative, observational, retrospective, and multicenter Spanish study included patients receiving outpatient parenteral antimicrobial therapy (OPAT) and hospitalized patients treated for at least 48 h with ceftaroline-F or ceftobiprole-M between their first incorporation in the clinical protocol of each hospital and 31 July 2022. Results: Ceftaroline-F was administered to 227 patients and ceftobiprole-M to 212. In comparison to the latter, ceftaroline-F-treated participants were younger (63.02 vs. 66.40 years, OR 1.1; 95%CI: 1.001–1.05) and had higher rates of septic shock (OR 0.27; 95%CI: 0.09–0.81) and higher frequencies of targeted (57.7 vs. 29.7%; OR: 0.35; 95%CI: 0.18–0.69) and combined (89.0 vs. 45.8%, OR: 0.13; 95%CI: 0.06–0.28) therapies that were second line or more (82.4% vs. 64.6%%; OR 0.35; 95%CI: 0.18–0.69), and higher rates of infections due to Gram-positive cocci (92.7 vs. 64.7%, p = 0.001), bacteremia (51.9 vs. 21.7%, p = 0.001), infective endocarditis (24.2 vs. 2.4%, p = 0.0001), and mechanical ventilation-associated pneumonia (8.8 vs. 2.4%, p = 0.0001). Ceftobiprole-M was more frequently administered against polymicrobial infections (38.1 vs. 14.0%, p = 0.001), those produced by Gram-negative bacilli (19.7 vs. 6.0%, p = 0.0001), nosocomial pneumonia (33 vs. 10.6%, p = 0.0001), and skin and soft-tissue infections (25.4 vs. 10.1%, p = 0.0001). Patients treated with ceftaroline-F had a longer hospital stay (36 (IQR: 19–60) vs. 19.50 (IQR: 12–30.75, p = 0.0001) days), with no difference in infection-related mortality at 14 (13.2 vs. 8.0%, p = 0.078) or 28 (4.8 vs. 3.3%, p = 0.415) days or in dropout rate for adverse effects (2.2 vs. 0.9%; p = 1). Conclusions: The fifth-generation cephalosporins, ceftaroline-F and ceftobiprole-M, are safe and effective in real life, with no difference between them in health outcomes.
1. Introduction
The increase in antimicrobial resistance is one of the main public health threats worldwide, including in Europe and Spain [1]. The rise of multiresistant microorganisms is associated with higher health costs, more frequent antibiotic treatment failures, quality of life impairment, and increased mortality [2]. The latest World Health Organization report on antimicrobial resistance in 2020 described a 16.6% prevalence of carbapenem-resistant Pseudomonas aeruginosa and a 23.3% prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in Spain, with the latter being above the European mean of 16.7% [3]. These data underscore the need for a carbapenem-sparing strategy in our setting, using bactericides other than carbapenems in patients with sepsis or septic shock, such as fifth-generation cephalosporins: ceftaroline-F and ceftobiprole-M.
Ceftaroline-F exerts high bactericide activity against Gram-positive cocci (GPC) such as Streptococcus pneumoniae (including third-generation cephalosporin-resistant species), beta-hemolytic Streptococci, and Staphylococcus aureus (SA), including MRSA [4]. Its spectrum against Gram-negative bacilli (GNB) is comparable to that of third-generation cephalosporins and includes Hemophilus influenzae, Moraxella catarrhalis, and most Enterobacteriaceae [5]. The majority of nonfermenting GNBs are resistant, including Pseudomonas aeruginosa [5,6]. The European Agency has approved ceftaroline-F for community-acquired pneumonia (CAP) and acute bacterial skin and soft-tissue infections (ABSSTIs) [7,8]. Given its pharmacokinetics and pharmacodynamics, it may be a useful alternative option against bacteremia, infective endocarditis (IE), nosocomial pneumonia (NP), and osteoarticular infections [9,10], especially in cases of therapeutic failure or resistance to other antibiotics, such as vancomycin or daptomycin [11].
Ceftobiprole-M exerts bactericide activity against GPC (SA, including MRSA, coagulase-negative Staphylococci (CoNS), Streptococci spp., and ampicillin-susceptible Enterococcus faecalis and E. faecium), and Gram-negative bacteria (GNB), including Hemophilus influenzae, Moraxella catarrhalis, and Pseudomonas aeruginosa [12]. It is, therefore, suitable for treating bacteremia, IE, ABSSTIs, and complicated urinary infections [13]. Experimental and animal models of staphylococcal infections in biofilms found their bactericide capacity to be higher than linezolid, vancomycin, and daptomycin [14,15]. These properties make them especially useful against infections associated with devices, endoprostheses, osteosynthesis material, or prosthetic valves. However, they are only authorized for CAP and NP in Europe [16,17], despite demonstrating their non-inferiority against ABSSTIs in comparison to comparators [18].
Clinical trials are evidently the gold standard for the approval and commercialization of novel pharmaceutical compounds; however, extrapolation of their outcomes is limited by the strict inclusion criteria and special conditions imposed [19]. The aim of real-life studies (Real World Data (RWD)) is to bridge the knowledge gap between clinical trials and clinical practice. This type of study has served to reduce medical costs, improve outcomes, and accelerate the incorporation of novel therapies and technologies into routine clinical practice [20].
Given this background and the limited scientific evidence available on fifth-generation cephalosporins, the objective of this study was to compare real-life effectiveness and safety between ceftaroline-F and ceftobiprole-M in the treatment of the principal infectious syndromes in hospitalized patients in Spain.
2. Results
2.1. Cohort Description
This study included 227 patients treated with ceftaroline-F and 212 treated with ceftobiprole-M. In bivariate analyses, patients receiving ceftaroline-F were younger (63.02 vs. 66.4 years, p = 0.015), more frequently had cardiovascular risk factors (74 vs. 49.1%, p = 0.001), cardiovascular disease (atrial fibrillation (16.3 vs. 8.5% p = 0.014), and moderate–severe heart valve disease (18.9 vs. 4.2%, p = 0.001)) and were more frequently solid organ transplant recipients (10.1 vs. 2.4%; p = 0.001), were in the Intensive Care Unit (ICU) (20.3 vs. 4.7%; p = 0.001) or post-surgery unit (8.5 vs. 0.0%, p = 0.0001), and were in septic shock (21.1 vs. 4.2%, p = 0.001). Patients administered ceftobiprole-M had a significantly higher rate of solid organ neoplasm under active treatment (7.1 vs. 2.6%, p = 0.030) and sepsis (16.7 vs. 25%; p = 0.033) and more frequently received outpatient parenteral antimicrobial therapy (OPAT) (3.8 vs. 0.0%, p = 0.003). In multivariate analysis, ceftaroline-treated patients were younger (63.02 vs. 66.40 years, OR 1.1; 95%CI: 1.001–1.05) and had higher rates of septic shock (OR 0.27; 95%CI: 0.09–0.81) and higher frequencies of targeted (57.7 vs. 29.7%; OR: 0.35; 95%CI: 0.18–0.69) and combined (89.0 vs. 45.8%, OR: 0.13; 95%CI: 0.06–0.28) therapies that were second line or more (82.4% vs. 64.6%%; OR 0.35; 95%CI: 0.18–0.69). Table 1 lists the results for the remaining study variables.
Ceftaroline-F was prescribed more frequently for bacteremia (51.9 vs. 21.7%; p = 0.001), IE (24.2 vs. 2.4%; p = 0.001), IMVAP (8.8 vs. 2.4%; p = 0.001), and fever without focus (3.5 vs. 0%, p = 0.003) and less frequently for respiratory infections (45.4 vs. 66%, p = 0.006), NP (10.6 vs. 33%; p = 0.001), and ABSSTIs (10.1 vs. 25.4%, p = 0.0001) (Table 2).
Patients treated with ceftaroline-F received a higher drug concentration (11.7 g (IQR 6.6–19.8 g) vs. 11 g (IQR 6.25–15 g, p = 0.015)) for a longer time (8 days (IQR 5–14 day) vs. 7 days (IQR 5–10 days, p = 0.023)), and it was more frequently administered in combination (89 vs. 45.8%, p = 0.001) as a targeted therapy (57.7 vs. 29.7%, p = 0.001) and as a rescue therapy after the failure of another antibiotic (82.4 vs. 64.6%, p = 0.001) (Table 1). Ceftaroline-F was most frequently combined with daptomycin (36.4%), meropenem (20.8%), and metronidazole (20.8%) (Supplementary Table S1), and the antibiotics most often received before ceftaroline-F were daptomycin (33.7%), meropenem (27.9%), and linezolid (20%) (Supplementary Table S2).
2.2. Microbiological Isolation
Among patients treated with ceftaroline-F, microorganisms were isolated in 150 infectious episodes (66.1%), 21 (14%) of which were polymicrobial. Among those treated with ceftobiprole-M, microorganisms were isolated in 139 episodes (65.5%), of which 53 (38.1%) were polymicrobial, a statistically significant difference (p = 0.0001) (Table 3).
Microorganisms isolated in ceftaroline-F-treated patients were GPC in 139 (92.7%), thirty-nine (26%) of which were MRSA; methicillin-susceptible Staphylococcus aureus (MSSA) in thirty-one (20.7%); GNB in nine (6%), of which eight (5.3%) were multi-susceptible Enterobacteriaceae (five Escherichia coli, two Klebsiella pneumoniae, and one Providencia stuarti); and nonfermenting GNB (Hemophilus influenzae) in one (Supplementary Table S2). Microorganisms isolated in ceftobiprole-M-treated patients were GPC in ninety (64.7%), of which twenty-five (18%) were MRSA and twenty-one (15.1%) were MSSA; methicillin-resistant CoNS in forty (26.7%); and GNB in forty-eight (19.7%), of which twekve (8.6%) were multi-susceptible Enterobacteriaceae (four Escherichia coli, five Klebsiella pneumoniae, one Proteus vulgaris, one Proteus mirabilis, and one Klebsiella oxytoca), Pseudomonas aeruginosa in thirty-two (23%), and other nonfermenting GNB in four (2.9%) (two Morganella morganii, one Moraxella catarrhalis, and one Haemophilus influenzae).
All GPC isolates in the ceftaroline-F group (n = 113) were susceptible to vancomycin vs. 96.4% of GPC isolates in the ceftobiprole-M group (n = 53) (p = 0.106), with one Staphylococcus hominis and one MRSA being vancomycin resistant.
All tested microorganisms in the ceftaroline-F group (forty-three microorganisms: thirteen MRSA, 12 MSSA, eleven Staphylococcus epidermidis, three Staphylococcus hominis, two Staphylococcus lungdunensis, one Staphylococcus capitis, and one Staphylococcus xylosus) and in the ceftobiprole-M group (twenty-one microorganisms: three MSSA, three MRSA, four Pseudomonas aeruginosa, two Staphylococcus epidermidis, one Staphylococcus haemolyticus, one Proteus mirabilis, one Klebsiella pneumoniae, one Escherichia coli, one Streptococcus anginosus, one Enterococcus faecalis, one Morganella morganii, one Proteus vulgaris, and one Klebsiella oxytoca) were susceptible to both antibiotics.
2.3. Health Outcomes
Patients treated with ceftaroline-F had a longer hospital stay (36 days [IQR 19–60] vs. 19.5 days (IQR 12–30.75)). Total crude mortality and infection-related mortality rates were higher in the ceftaroline-F group (33.9 vs. 21.2%, p = 0.003, 18.9 vs. 11.8%, p = 0.039, respectively), although there was no difference in the mortality at 14 (13.2 vs. 8.0%, p = 0.078) or 28 days (4.8 vs. 3.3%, p = 0.415). A lower percentage of hospital readmissions for the same motive was observed in ceftaroline-Fvs. ceftobiprole-M-treated patients (1.3 vs. 4.7%, p 0.003). Relapses were recorded in 0% of ceftaroline-F-treated patients vs. 1.4% of ceftobiprole-M-treated patients (p = 0.072) (Table 4).
The infection-related mortality rate did not differ between the antibiotics by type of infection (Figure 1) or microbiological isolate (Figure 2).
Infective Endocarditis
Among the sixty patients with IE, fifty-five (91.6%) received ceftaroline-F and only five (8.3%) received ceftobiprole-M. Defined IE was present in 37 (67.3%) of the patients treated with ceftaroline-F. The IE type most frequently treated with ceftaroline-F was native valve-related (45.5%), followed by early prosthetic (18.2%), late prosthetic (12.7%), and device-related (10.9%) IE; surgery was performed in 21 ceftaroline-F-treated patients with IE (38.2%) and was prescribed but not performed in 11 (20%) due to their clinical status or technical infeasibility. The most frequently isolated microorganisms in these patients were SA (40%), with an MRSA rate of 27.3%, and CoNS (38.2%), with a Staphylococcus epidermidis rate of 29.1%. The global mortality rate was 40%, and the infection-related mortality rate was 23.6% (Table 5).
2.4. Adverse Effects
No adverse effects were observed in 96% of the patients treated with ceftaroline-F or 97.6% of those treated with ceftobiprole-M. In the former, mild effects were recorded in three patients (1.3%) and moderate effects in six (2.5%), while withdrawal of the antibiotic was mandated in five (2.1%). In the five patients treated with ceftobiprole-M, adverse effects were mild in three (1.4%), moderate in two (0.9%), and caused withdrawal of the antibiotic in two (0.9%) (Table 6).
2.5. Mortality Risk Factors by Antibiotic
Infection-related mortality risk factors in the ceftaroline-F group were a history of cardiovascular disease (53.5 vs. 24.0%, p 0.018), bacteremia (54.5 vs. 17.2%, p 0.001), IE (29.5 vs. 3.4%, p 0.006), and infection by GPC (100 vs. 64.3%, p = 0.002). Infection-related mortality risk factors in the ceftobiprole-M group were advanced age (75.88 ± 13.64 years vs. 65.84 ± 10.50 years, p = 0.001), the presence of CAP (41.4 vs. 13.6%, p = 0.007) or NP (31.0 vs. 11.4%, p = 0.037), polymicrobial infection (50.0 vs. 8.3%, p = 0.004), infection due to GNB (35.7 vs. 0.0%, p = 0.004) or Pseudomonas (35.7 vs. 0.0%, p = 0.002), monotherapy (56.0 vs. 7.0%, p = 0.0001), and empirical administration (84.0 vs. 46.5%, p 0.002). In the multivariate analysis, no differences were found between ceftarolineand ceftobiprole-treated patients whose death was directly attributable to their infection (Table 7).
3. Discussion
The patients in our cohort were mostly males with a high comorbidity index, and all were aged > 60 years. The ceftaroline-treated patients were younger, their clinical status was worse, and they more frequently received targeted and combined second-line treatments or more. Both ceftaroline and ceftobiprole were most often combined with daptomycin. Previous studies have demonstrated the clinical benefit of combining these fifth-generation cephalosporins with daptomycin in bacteriemia due to MRSA [21,22]. Around one in four patients were hospitalized in medical departments, with 20% of ceftaroline-F-treated patients and 5% of ceftobiprole-M-treated patients being in the ICU. More than half of the infections were nosocomial or healthcare-related, and around one-third of them met the criteria for sepsis. Septic shock, reported by some authors to increase the mortality risk by up to 40% [23], was five-fold more prevalent among the ceftaroline-F-treated patients in our cohort.
Ceftaroline-F was most frequently prescribed to treat bacteremia, IE, ABSSTIs, or pneumonia. The IMVAP healing rate was 80%, similar to previous reports [24]. In comparison to the rates obtained with ceftaroline-F treatment in the multicenter CAPTURE study of more than 500 patients with pneumonia, the cure rate was slightly higher in the present patients with CAP (89.2 vs. 79%), lower in those with chronic obstructive pulmonary disease (COPD) (15 vs. 40%) [24], and similar in those with NP (80%) and IMVAP (60%) [25]. In the patients with IE treated with ceftaroline-F, the related mortality was 23.6%, lower than in the CAPTURE study (34.3%) [26], despite having a similar percentage of patients with IE due to SA (40 vs. 35.8%, respectively), and in surgery-indicated patients who did not undergo surgery (20% vs. 19.5%). It has previously been observed [27] that the isolation of MSSA and the indication but non-performance of surgery are associated with a higher mortality in patients with IE.
Ceftobiprole-M was prescribed against pneumonia in more than half of the patients, ABSSTIs in around one-fifth, and bacteremia in around one-sixth. Among the cases of pneumonia treated with ceftobiprole-M, around half were CAP and half NP, with only five cases of IMVAP. This fifth-generation cephalosporin has demonstrated non-inferior clinical effectiveness and safety with respect to its comparators in various clinical trials for the treatment of ABSSTIs [28], complicated S. aureus bacteriemia (ERADICATE study) [29], CAP, and NP [16,17]. However, worse outcomes have been obtained in patients with IMVAP treated with ceftobiprole-M vs. ceftazidime plus linezolid [17], and ceftobiprole-M is, therefore, not indicated for its treatment [30]. Recently, a real-life study has reported on the use of ceftobiprole-M for severe infections in a French ICU, finding that the main indication for this antibiotic was pneumonia (51%) with associated bacteremia (72%); clinical cure was achieved in around 80% of patients, with an in-hospital mortality rate of 32% [31].
One in ten patients with pneumonia in our study, including both ceftobiprole-Mand ceftaroline-F-treated patients, were coinfected with COVID-19. COVID-19 coinfection and suprainfection have been associated with a worse clinical prognosis in patients with respiratory infection, increasing the mortality risk by up to three-fold [32].
The infection-related mortality rate at 14 and 18 days did not differ between the ceftarolineand ceftobiprole-treated patients, and no between-group differences in age, sex, previous disease, infection type, or isolated microorganism were observed among those whose death was attributable to the infection. Mortality risk factors were older age, Charlson index, ICU stay, and the presence of sepsis and septic shock in both antibiotic groups. This is consistent with published evidence that age, comorbidity, ICU admission (and duration), and septic shock are independent prognostic factors for mortality in patients with sepsis [21,33,34]. The mortality rate of patients with IE treated with ceftaroline-F was 23.6%, although SA was the causal agent in two-fifths of these patients, and surgery was prescribed but not feasible in one-fifth. A previous study of patients with IE due to SA in our setting described a higher mortality rate of 50% that was not influenced by methicillin resistance [35].
The readmission rate was significantly higher among patients treated with ceftobiprole-M but below 5% for both antibiotics (4.7 vs. 1.3%, p = 0.036). Seven of the ten ceftobiprole-M-treated patients readmitted had ABSSTIs, which have previously been associated with a recurrence rate of around 10% [36]. However, interpretation of the results should take account of disparities between the antibiotic cohorts (in previous diseases, pathways, and microorganisms) that may diminish the comparability of outcomes.
No adverse effects were observed in 96% of patients receiving ceftaroline-F or in 97.6% of those receiving ceftobiprole-M. These data are similar to the findings of clinical trials [8,17,37] and real-life studies [22,38,39], in which the most frequent effects in these studies were gastrointestinal, cutaneous, and hepatic profile disorders, with the less common observation of myoclonia with ceftobiprole-M [38] and cytopenia with ceftaroline-F [40]. Cytopenia was observed in three of our ceftaroline-F-treated patients. Currently, a retrospective, single-center study has just been published, conducted in an Italian hospital, which compared in real life the effectiveness of the use of ceftaroline-M vs. ceftobiprole in a reduced number of subjects (75 vs. 63 patients), with data similar to ours in terms of clinical efficacy and tolerability [41].
This study is limited by its retrospective design and associated selection bias, which may influence the results obtained and their interpretation. However, this is the first real-life comparative study of ceftaroline-F and ceftobiprole-M and has a wide patient sample from different centers, representing as far as possible the routine clinical utilization of these fifth-generation cephalosporins in Spain.
4. Materials and Methods
4.1. Study Design
A real-life, retrospective, multicenter, observational, descriptive study was conducted on the use of ceftaroline-F and ceftobiprole-M in hospitalized patients or outpatient parenteral antimicrobial therapy (OPAT) with nosocomial/nosohusial or community-acquired infections. Patients were included between the date that these drugs were incorporated in the clinical protocol of the participating hospital and 31 July 2022. The study was approved by the provincial ethics committee of Granada (Ref. 0095-N-22) and deemed exempt from the requirement for informed patient consent.
4.2. Treatment Description
This descriptive study did not involve any pharmacological intervention, and all treatments were prescribed by the attending physicians according to their habitual criteria. Inclusion criteria were age ≥ 18 years; at least 48 h of antibiotic treatment with ceftaroline-F or ceftobiprole-M (≥6 vials in patients with normal renal function and creatinine clearance-adjusted dosage in patients with kidney failure) between the date of drug approval at the hospital and 31 July 2022; and the completion of a 28-day follow-up, except for patients with IE or osteomyelitis (6-month follow-up). Exclusion criteria were pregnancy and allergy to beta-lactams or some formulation excipient.
4.3. Variables
Data were gathered on sex, age, hospital stay, prescribing hospital department, patient comorbidities, infection acquisition pathway, and the presence of sepsis or septic shock. The age-corrected Charlson index was calculated for each patient [42].
Information was also collected on the number of active infectious foci, the presence of bacteremia (primary/catheter-related) and IE (by modified Duke’s diagnostic criteria [43] (defined/possible/rejected–suspicion), the type of IE (native valve/early prosthetic/late prosthetic/pacemaker or device/transcatheter aortic valve implantation, the performance of surgery (not indicated/indicated but not undergone/device extraction)), and the presence of respiratory infection (CAP/NP/invasive mechanical ventilation-associated pneumonia (IMVAP)), ABSSTI, urinary tract infection, central nervous system infection, spondylodiscitis, osteoarticular infection, intraabdominal infection, fever with no focus, and other infectious foci. For respiratory infections, data were recorded on coinfection by coronavirus SARS-2 2019 and suspected or confirmed fungal coinfection.
Treatment details were collected on the prescribed antibiotic (ceftaroline-F or ceftobiprole-M); the mode of administration, monotherapy or a combination with other antibiotics against the same infection, empirical or targeted, first-line or rescue treatment (in the latter case, specifying previous antibiotic therapy for the same infection and its duration); reason for antibiotic rescue (previous antibiotic treatment failure/receipt of indicative microbiological results/emergence of toxicity or adverse effects with previous treatments) and appropriate empirical antibiotic therapy (i.e., effective against isolated microorganisms or good clinical outcome if none are isolated); and the total days of antibiotic administration, total administered dose, and the presence, type, and severity of adverse effects.
Microbiology data were collected on the monoor poly-microbial nature of the infection; the microorganism(s) identified; and the antibiogram, in accordance with EUCAST criteria [44]. MIC cutoffs (mg/L) by genus were Staphylococcus (two vancomycin (SA), five vancomycin (CoNS), two oxacillin (SA), 0.25 oxacillin (CoNS)); Enterococcus (four vancomycin); Streptococcus pneumoniae (1 cefepime; 0.5 ceftobiprole; two vancomycin; two meropenem); Enterobacteriaceae (1 cefepime; 0.25 ceftobiprole; two meropenem); and Pseudomonas aeruginosa (0.001 cefepime; ceftobiprole: insufficient evidence; two meropenem). The studied microorganisms were isolates obtained in conventional culture media, including hemocultures and cultures of urine, cerebrospinal fluid, bone, and abscesses from patients during an infectious episode treated with either antibiotic.
The following health outcomes were recorded: clinical cure, total crude mortality at 14 and 28 days (6 months for patients with IE or osteomyelitis), infection-related mortality, readmission for the same motive, and infection recurrence.
4.4. Definitions
Nosocomial/Nosohusial infection: infection in patients hospitalized for >72 h (nosocomial) or healthcare-related infection (day hospital, nursing home, day center for the elderly). Septic shock: refractory hypotension accompanied by hypoperfusion and organ dysfunction despite adequate fluid resuscitation [45]. Immunosuppression: congenital or acquired immunodeficiency (including oncohematological patients) or secondary to immunosuppressive treatment [46]. Recurrence/relapse: the second microbiologically confirmed episode of the infection within one month of discharge [47]. Severity of adverse effects: mild = no requirement for antidote or treatment; moderate = requirement for treatment modification (e.g., dose adjustment, combination with other drugs) but not an interruption, with possible need for a longer hospital stay or specific treatment prescription; severe = life threatening, mandating an interruption of drug administration and the prescription of a specific treatment; or lethal = directly or indirectly contributing to death.
Data were gathered from the different electronic records systems of participating hospitals by obtaining the records of patients receiving the drugs from the hospital Pharmacy Departments. Data were anonymized before being entered into the SPSS 20.0 database in accordance with the Helsinki Declaration and Spanish data protection legislation (Law 3/2018 5 December).
4.5. Sample Size
This descriptive comparative study included all patients meeting study eligibility criteria treated with ceftaroline-F or ceftobiprole-M at participating centers during the study period.
4.6. Statistical Analysis
In a descriptive analysis, absolute and relative frequencies (%) with a 95% confidence interval (CI) were calculated for qualitative variables, means with standard deviation (SD) for quantitative variables with a normal distribution (Kolmogorov–Smirnov test), and medians with an interquartile range (IQR) for those with a non-normal distribution. In bivariate analyses, the chi-square test was used to compare qualitative variables, Student’s t-test was used for quantitative variables with normal distributions, and the Mann–Whitney U test was used for quantitative variables with non-normal distributions.
A logistic regression multivariate analysis was performed to examine between-group differences in epidemiologic variables, medical history of interest, drug dose, and drug administration (alone/in combination) and its prescription as empirical, targeted, or rescue therapy (with reason for rescue) by entering all variables that were statistically significant in bivariate analysis. Another regression analysis was carried out to evaluate mortality-related factors in the two antibiotic groups.
5. Conclusions
The fifth-generation cephalosporins, ceftaroline-F and ceftobiprole-M, are safe and effective in real life, with no difference between them in health outcomes.
Supplementary Materials
The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/antibiotics12121692/s1, Table S1: Combined antibiotic therapy with ceftaroline or ceftobiprole; Table S2: Previous antibiotic therapy before prescription of ceftaroline or ceftobiprole.
Author Contributions
Conceptualization, D.A.G. and C.H.-T.; methodology, C.H.-T.; software, D.A.G., I.P.-R., J.C.P., M.C.S., C.H.R. and L.G.; validation, I.P.-R., formal analysis, C.H.-T. and D.A.G.; investigation, C.H.-T.; resources C.H.-T., data curation, D.A.G. and I.P.-R.; writing—original draft preparation, D.A.G.; writing—review and editing, C.H.-T.; visualization, J.C.P., M.C.S., C.H.R. and L.G., supervision, J.C.P., M.C.S., C.H.R. and L.G.; project administration, D.A.G. and I.P.-R. All authors have read and agreed to the published version of the manuscript.
Funding
The project received partial funding from the laboratory Basilea Pharmaceutica International Ltd., Allschwil, Hegenheimermattweg 167b, Switzerland.
Institutional Review Board Statement
This study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Granada (CEIM/CEI of Granada); code: 0095-N-22.
Informed Consent Statement
This study was exempt from the need to obtain patient consent due to its retrospective design and large size.
Data Availability Statement
The authors confirm the accuracy and availability of the data used in this study.
Acknowledgments
The authors would like to thank the collaborating researchers for their help in carrying out this project. Collaborators: Svetlana Sadyrbaeva-Dolgova (1), Esther Calbo (2), Aina Mateu Subirà,(2), Francisco Javier Membrillo de Novales (3), Laura Morata (4), Raul Mendez (5), Olga Bravo de Pablo (6), Vicente Abril López de Medrano (7), Miguel Salavert Lleti (8), Pilar Vizcarra (9), Jaime Lora-Tamayo (10), Ana Arnáiz García (11), Leonor Moreno Núñez (12), Mar Masiá (13), Maria Pilar Ruiz Seco (14), Affiliations: Servicio de Farmacia Hospital Virgen de las Nieves, Instituto de Investigación Biosanitario de Granada (IBS-Granada) (1), Unidad de Enfermedades Infecciosas, Hospital Universitario Mútua de Terrassa (Barcelona) (2), CBRN y Enfermedades Infecciosas, Hospital General Defensa Gómez Ulla (Madrid) (3), Servicio de Enfermedades Infecciosas, Hospital Clinic Barcelona (4), Servicio de Neumología, Hospital Universitario La Fe (Valencia) (5), Servicio de Medicina Interna, Hospital La Moraleja (Madrid) (6), Servicio de Enfermedades Infecciosas, Hospital General de Valencia (7), Hospital La Fe de Valencia (8), Servicio de Enfermedades Infecciosas Hospital Ramón y Cajal (Madrid) (9), Servicio de Medicina Interna, Hospital 12 Octubre (Madrid) (10), Servicio de Enfermedades Infecciosas, Hospital Sierrallana (Torrelavega, Cantabria) (11), Servicio de Medicina Interna, Hospital Fundación de Alcorcón (Madrid) (12), Servicio de Enfermedades Infecciosas, Hospital General Universitario de Elche (Alicante) (13), Servicio de Medicina Interna, Hospital Infanta Sofía (Madrid) (14).
Conflicts of Interest
The authors declare no conflict of interest. The funders had no role in the design of the study or the collection of the information.
References
- Murray, C.J.; Ikuta, K.S.; Sharara, F.; Swetschinski, L.; Aguilar, G.R.; Gray, A.; Han, C.; Bisignano, C.; Rao, P.; Wool, E.; et al. Global burden of bacterial antimicrobial resistance in 2019: A systematic analysis. Lancet 2022, 399, 629–655. [Google Scholar] [CrossRef] [PubMed]
- Cassini, A.; Högberg, L.D.; Plachouras, D.; Quattrocchi, A.; Hoxha, A.; Simonsen, G.S.; Colomb-Cotinat, M.; Kretzschmar, M.E.; Devleesschauwer, B.; Cecchini, M.; et al. Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015: A population-level modelling analysis. Lancet Infect. Dis. 2019, 19, 56–66. [Google Scholar] [CrossRef] [PubMed]
- ECDC. Antimicrobial Resistance Surveillance in Europe, 2022–2020 Data. Available online: https://www.ecdc.europa.eu/en/publications-data/antimicrobial-resistance-surveillance-europe-2022-2020-data (accessed on 6 August 2023).
- Farrell, D.J.; Castanheira, M.; Mendes, R.E.; Sader, H.S.; Jones, R.N. In vitro activity of ceftaroline against multidrug-resistant Staphylococcus aureus and Streptococcus pneumoniae: A review of published studies and the AWARE Surveillance Program (2008–2010). Clin. Infect. Dis. 2012, 55 (Suppl. S3), 206–214. [Google Scholar] [CrossRef] [PubMed]
- Jean, S.S.; Lee, W.S.; Ko, W.C.; Hsueh, P.R. In vitro susceptibility of ceftaroline against clinically important Gram-positive cocci, Haemophilus species and Klebsiella pneumoniae in Taiwan: Results from the Antimicrobial Testing Leadership and Surveillance (ATLAS) in 2012–2018. J. Microbiol. Immunol. Infect. 2021, 54, 627–631. [Google Scholar] [CrossRef] [PubMed]
- Laudano, J.B. Ceftaroline fosamil: A new broad-spectrum cephalosporin. J. Antimicrob. Chemother. 2011, 66 (Suppl. S3), 11–18. [Google Scholar] [CrossRef] [PubMed]
- Taboada, M.; Melnick, D.; Iaconis, J.P.; Sun, F.; Zhong, N.S.; File, T.M.; Llorens, L.; Friedland, H.D.; Wilson, D. Ceftaroline fosamil versus ceftriaxone for the treatment of community-acquired pneumonia: Individual patient data meta-analysis of randomized controlled trials. J. Antimicrob. Chemother. 2016, 71, 862–870. [Google Scholar] [CrossRef]
- Corey, G.R.; Wilcox, M.H.; Talbot, G.H.; Thye, D.; Friedland, D.; Baculik, T. CANVAS 1: The first Phase III, randomized, double-blind study evaluating ceftaroline fosamil for the treatment of patients with complicated skin and skin structure infections on behalf of the CANVAS 1 investigators. J. Antimicrob. Chemother. 2010, 65, 41–51. [Google Scholar] [CrossRef]
- Athans, V.; Kenney, R.M.; Wong, J.; Davis, S.L. Outpatient use of ceftaroline fosamil versus vancomycin for osteoarticular infection: A matched cohort study. J. Antimicrob. Chemother. 2016, 71, 3568–3574. [Google Scholar] [CrossRef]
- Pani, A.; Colombo, F.; Agnelli, F.; Frantellizzi, V.; Baratta, F.; Pastori, D.; Scaglione, F. Off-label use of ceftaroline fosamil: A systematic review. Int. J. Antimicrob. Agents 2019, 54, 562–571. [Google Scholar] [CrossRef]
- Cosimi, R.A.; Beik, N.; Kubiak, D.W.; Johnson, J.A. Ceftaroline for Severe Methicillin-Resistant Staphylococcus aureus Infections: A Systematic Review. Open Forum Infect. Dis. 2017, 4, ofx084. [Google Scholar] [CrossRef]
- Pérez-Crespo, P.M.M.; Cortés, L.E.L. Ceftobiprole: A clinical view. Rev. Española Quimioter. 2021, 34, 32. [Google Scholar] [CrossRef]
- Lupia, T.; Pallotto, C.; Corcione, S.; Boglione, L.; De Rosa, F.G. Ceftobiprole Perspective: Current and Potential Future Indications. Antibiotics 2021, 10, 170. [Google Scholar] [CrossRef]
- Rouse, M.S.; Steckelberg, J.M.; Patel, R. In vitro activity of ceftobiprole, daptomycin, linezolid, and vancomycin against methicillin-resistant staphylococci associated with endocarditis and bone and joint infection. Diagn. Microbiol. Infect. Dis. 2007, 58, 363–365. [Google Scholar] [CrossRef] [PubMed]
- Abbanat, D.; Shang, W.; Amsler, K.; Santoro, C.; Baum, E.; Crespo-Carbone, S.; Lynch, A.S. Evaluation of the in vitro activities of ceftobiprole and comparators in staphylococcal colony or microtitre plate biofilm assays. Int. J. Antimicrob. Agents 2014, 43, 32–39. [Google Scholar] [CrossRef]
- Nicholson, S.C.; Welte, T.; File, T.M., Jr.; Strauss, R.S.; Michiels, B.; Kaul, P.; Balis, D.; Arbit, D.; Amsler, K.; Noel, G.J. A randomised, double-blind trial comparing ceftobiprole medocaril with ceftriaxone with or without linezolid for the treatment of patients with community-acquired pneumonia requiring hospitalisation. Int. J. Antimicrob. Agents 2012, 39, 240–246. [Google Scholar] [CrossRef] [PubMed]
- Awad, S.S.; Rodriguez, A.H.; Chuang, Y.C.; Marjanek, Z.; Pareigis, A.J.; Reis, G.; Scheeren, T.W.; Sánchez, A.S.; Zhou, X.; Saulay, M.; et al. A phase 3 randomized double-blind comparison of ceftobiprole medocaril versus ceftazidime plus linezolid for the treatment of hospital-acquired pneumonia. Clin. Infect. Dis. 2014, 59, 51–61. [Google Scholar] [CrossRef]
- Overcash, J.S.; Kim, C.; Keech, R.; Gumenchuk, I.; Ninov, B.; Gonzalez-Rojas, Y.; Waters, M.; Simeonov, S.; Engelhardt, M.; Saulay, M.; et al. Ceftobiprole Compared with Vancomycin Plus Aztreonam in the Treatment of Acute Bacterial Skin and Skin Structure Infections: Results of a Phase 3, Randomized, Double-blind Trial (TARGET). Clin. Infect. Dis. 2021, 73, e1507–e1517. [Google Scholar] [CrossRef] [PubMed]
- Blonde, L.; Khunti, K.; Harris, S.B.; Meizinger, C.; Skolnik, N.S. Interpretation and Impact of Real-World Clinical Data for the Practicing Clinician. Adv. Ther. 2018, 35, 1763–1774. [Google Scholar] [CrossRef]
- Berger, M.L.; Sox, H.; Willke, R.J.; Brixner, D.L.; Eichler, H.G.; Goettsch, W.; Madigan, D.; Makady, A.; Schneeweiss, S.; Tarricone, R.; et al. Good Practices for Real-World Data Studies of Treatment and/or Comparative Effectiveness: Recommendations from the Joint ISPOR-ISPE Special Task Force on Real-World Evidence in Health Care Decision Making. Value Health 2017, 20, 1003–1008. [Google Scholar] [CrossRef]
- Geriak, M.; Haddad, F.; Rizvi, K.; Rose, W.; Kullar, R.; LaPlante, K.; Yu, M.; Vasina, L.; Ouellette, K.; Zervos, M.; et al. Clinical Data on Daptomycin plus Ceftaroline versus Standard of Care Monotherapy in the Treatment of Methicillin-Resistant Staphylococcus aureus Bacteremia. Antimicrob. Agents Chemother. 2019, 63, e02483-18. [Google Scholar] [CrossRef]
- Barber, K.E.; Werth, B.J.; Ireland, C.E.; Stone, N.E.; Nonejuie, P.; Sakoulas, G.; Pogliano, J.; Rybak, M.J. Potent synergy of ceftobiprole plus daptomycin against multiple strains of Staphylococcus aureus with various resistance phenotypes. J. Antimicrob. Chemother. 2014, 69, 3006–3010. [Google Scholar] [CrossRef] [PubMed]
- Bauer, M.; Gerlach, H.; Vogelmann, T.; Preissing, F.; Stiefel, J.; Adam, D. Mortality in sepsis and septic shock in Europe, North America and Australia between 2009 and 2019—Results from a systematic review and meta-analysis. Crit. Care 2020, 24, 239. [Google Scholar] [CrossRef] [PubMed]
- Ramani, A.; Udeani, G.; Evans, J.; Jandourek, A.; Cole, P.; Smith, A.; David Friedland, H. Contemporary use of ceftaroline fosamil for the treatment of community-acquired bacterial pneumonia: CAPTURE study experience. J. Chemother. 2014, 26, 229–234. [Google Scholar] [CrossRef] [PubMed]
- Kaye, K.S.; Udeani, G.; Cole, P.; Friedland, H.D. Ceftaroline fosamil for the treatment of hospital-acquired pneumonia and ventilator-associated pneumonia. Hosp. Pract. 2015, 43, 144–149. [Google Scholar] [CrossRef]
- Destache, C.J.; Guervil, D.J.; Kaye, K.S. Ceftaroline fosamil for the treatment of Gram-positive endocarditis: CAPTURE study experience. Int. J. Antimicrob. Agents 2019, 53, 644–649. [Google Scholar] [CrossRef]
- Camazón, N.V.; Cediel, G.; Aragón, R.N.; Mateu, L.; Llibre, C.; Sopena, N.; Gual, F.; Ferrer, E.; Quesada, M.D.; Berastegui, E.; et al. Mortalidad a corto y largo plazo de pacientes con indicación quirúrgica no intervenidos en el curso de la endocarditis infecciosa izquierda. Rev. Esp. Cardiol. 2020, 73, 734–740. [Google Scholar] [CrossRef]
- Lan, S.H.; Lee, H.Z.; Lai, C.C.; Chang, S.P.; Lu, L.C.; Hung, S.H.; Lin, W.T. Clinical efficacy and safety of ceftobiprole in the treatment of acute bacterial skin and skin structure infection: A systematic review and meta-analysis of randomized controlled trials. Expert Rev. Anti-Infect. Ther. 2022, 20, 95–102. [Google Scholar] [CrossRef]
- Holland, T.L.; Cosgrove, S.E.; Doernberg, S.B.; Jenkins, T.C.; Turner, N.A.; Boucher, H.W.; Pavlov, O.; Titov, I.; Kosulnykov, S.; Atanasov, B.; et al. Ceftobiprole for Treatment of Complicated Staphylococcus aureus Bacteremia. N. Engl. J. Med. 2023, 389, 1390–1401. [Google Scholar] [CrossRef]
- Zevtera (Ceftobiprole). Product Monograph; AVIR Pharma Inc.: Blainville, QC, Canada, 2021; Available online: https://www.avirpharma.com/pdf/Product-Monograph-Zevtera.pdf (accessed on 6 August 2023).
- Bellut, H.; Arrayago, M.; Amara, M.; Roujansky, A.; Micaelo, M.; Bruneel, F.; Bedos, J.P. Real-life use of ceftobiprole for severe infections in a French intensive care unit. Infect. Dis. Now 2023, 27, 104790. [Google Scholar] [CrossRef]
- Musuuza, J.S.; Watson, L.; Parmasad, V.; Putman-Buehler, N.; Christensen, L.; Safdar, N. Prevalence and outcomes of co-infection and superinfection with SARS-CoV-2 and other pathogens: A systematic review and meta-analysis. PLoS ONE 2021, 16, e0251170. [Google Scholar] [CrossRef]
- Yang, Y.; Yang, K.S.; Hsann, Y.M.; Lim, V.; Ong, B.C. The effect of comorbidity and age on hospital mortality and length of stay in patients with sepsis. J. Crit. Care 2010, 25, 398–405. [Google Scholar] [CrossRef] [PubMed]
- Kim, S.M.; Ryoo, S.M.; Shin, T.G.; Park, Y.S.; Jo, Y.H.; Lim, T.H.; Chung, S.P.; Choi, S.H.; Suh, G.J.; Kim, W.Y.; et al. Prognostic factors for late death in septic shock survivors: A multi-center, prospective, registry-based observational study. Intern. Emerg. Med. 2022, 17, 865–871. [Google Scholar] [CrossRef] [PubMed]
- Hidalgo-Tenorio, C.; Gálvez, J.; Martínez-Marcos, F.J.; Plata-Ciezar, A.; De La Torre-Lima, J.; López-Cortés, L.E.; Noureddine, M.; Reguera, J.M.; Vinuesa, D.; García, M.V.; et al. Clinical and prognostic differences between methicillin-resistant and methicillin-susceptible Staphylococcus aureus infective endocarditis. BMC Infect. Dis. 2020, 20, 160. [Google Scholar] [CrossRef] [PubMed]
- Blasi, F.; Ostermann, H.; Racketa, J.; Medina, J.; McBride, K.; Garau, J.; REACH study group. Early versus later response to treatment in patients with community-acquired pneumonia: Analysis of the REACH study. Respir. Res. 2014, 15, 6. [Google Scholar] [CrossRef] [PubMed]
- Lodise, T.P.; Low, D.E. Ceftaroline fosamil in the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. Drugs 2012, 72, 1473–1493. [Google Scholar] [CrossRef]
- Durante-Mangoni, E.; Andini, R.; Mazza, M.C.; Sangiovanni, F.; Bertolino, L.; Ursi, M.P.; Paradiso, L.; Karruli, A.; Esposito, C.; Murino, P.; et al. Real-life experience with ceftobiprole in a tertiary-care hospital. J. Glob. Antimicrob. Resist. 2020, 22, 386–390. [Google Scholar] [CrossRef]
- Zhanel, G.G.; Kosar, J.; Baxter, M.; Dhami, R.; Borgia, S.; Irfan, N.; MacDonald, K.S.; Dow, G.; Lagacé-Wiens, P.; Dube, M.; et al. Real-life experience with ceftobiprole in Canada: Results from the CLEAR (Canadian Leadership on Antimicrobial Real-life usage) registry. J. Glob. Antimicrob. Resist. 2021, 24, 335–339. [Google Scholar] [CrossRef]
- Sullivan, E.L.; Turner, R.B.; O’Neal, H.R., Jr.; Crum-Cianflone, N.F. Ceftaroline-Associated Neutropenia: Case Series and Literature Review of Incidence, Risk Factors, and Outcomes. Open Forum Infect. Dis. 2019, 6, 168. [Google Scholar] [CrossRef]
- Zampino, R.; Gallo, R.; Salemme, A.; Marrazzo, T.; Iossa, D.; Karruli, A.; Andini, R.; Esitini, D.; Moretto, S.M.; De Gregorio, F.; et al. Clinical results with the use of ceftaroline and ceftobiprole: Real-life experience in a tertiary care hospital. Int. J. Antimicrob. Agents 2023, 62, 106883. [Google Scholar] [CrossRef]
- Charlson, M.E.; Charlson, R.E.; Peterson, J.C.; Marinopoulos, S.S.; Briggs, W.M.; Hollenberg, J.P. The Charlson comorbidity index is adapted to predict costs of chronic disease in primary care patients. J. Clin. Epidemiol. 2008, 61, 1234–1240. [Google Scholar] [CrossRef]
- Li, J.S.; Sexton, D.J.; Mick, N.; Nettles, R.; Fowler, V.G., Jr.; Ryan, T.; Bashore, T.; Corey, G.R. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin. Infect. Dis. 2000, 30, 633–638. [Google Scholar] [CrossRef] [PubMed]
- The European Committee on Antimicrobial Susceptibility Testing. Breakpoint Tables for Interpretation of MICs and Zone Diameters; Version 13.0; European Committee on Antimicrobial Susceptibility Testing: Växjö, Sweden, 2023. [Google Scholar]
- Cecconi, M.; Evans, L.; Levy, M.; Rhodes, A. Sepsis and septic shock. Lancet 2018, 392, 75–87. [Google Scholar] [CrossRef] [PubMed]
- Ramirez, J.A.; Musher, D.M.; Evans, S.E.; Cruz, C.D.; Crothers, K.A.; Hage, C.A.; Aliberti, S.; Anzueto, A.; Arancibia, F.; Arnold, F.; et al. Treatment of Community-Acquired Pneumonia in Immunocompromised Adults: A Consensus Statement Regarding Initial Strategies. Chest 2020, 158, 1896–1911. [Google Scholar] [CrossRef] [PubMed]
- Cisneros-Herreros, J.M.; Cobo-Reinoso, J.; Pujol-Rojo, M.; Rodríguez-Baño, J.; Salavert-Lletí, M. Guía para el diagnóstico y tratamiento del paciente con bacteriemia. Guías de la Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica (SEIMC). Enferm. Infecc. Microbiol. Clin. 2007, 25, 111–130. [Google Scholar] [CrossRef]
Figure 1.
Infection-related mortality by infection pathway.
Figure 2.
Mortality by microbial isolate.
Table 1.
Epidemiological characteristics, comorbidities, and antibiotic therapy.
| Ceftaroline (Cohort N = 227) | Ceftobiprole (Cohort N = 212) | p * | OR (95%CI) | |
|---|---|---|---|---|
| Age, mean (years) (± SD) | 63.02 (±13.45) | 66.40 (±15.44) | 0.015 | 1.1 (1.001–1.05) |
| Charlson index, mean (IQR) | 4 (2–6) | 4 (2–6) | 0.290 | |
| Men, n (%) | 140 (61.7) | 126 (59.4) | 0.631 | |
| Sepsis or septic shock, n (%) | 86 (37.9) | 62 (29.2) | 0.056 | |
| 38 (16.7) | 53 (25.0) | 0.033 | 6.7 (1.96–22.9) |
| 48 (21.1) | 8 (4.2) | 0.0001 | 0.27 (0.09–0.81) |
| Acquisition of infection, n (%) | ||||
| 109 (48.0) | 91 (42.9) | 0.284 | |
| 118 (52.0) | 121 (57.1) | ||
| Inpatient department, n (%) | 191 (84.1) | 169 (79.7) | 0.228 | |
| Medical departments, n (%) | 119 (62.3) | 134 (78.1) | 0.234 | |
| Surgical department, n (%) | 36 (18.8) | 35 (20.7) | 0.853 | |
| OPAT, n (%) | 0 (0.0) | 8 (3.8) | 0.003 | 0 (0–0) |
| Cardiovascular risk factors, n (%) | 168 (74.0) | 104 (49.1) | 0.0001 | 0.66 (0.19–2.3) |
| 123 (54.2) | 91 (42.9) | 0.018 | 1.4 (0.45–3.9) |
| 82 (36.1) | 55 (25.9) | 0.021 | 1.04 (0.5–2.2) |
| 80 (35.2) | 31 (14.6) | 0.0001 | 0.38 (0.16–0.87) |
| 21 (9.3) | 1 (0.5) | 0.0001 | 0 (0–0) |
| 30 (13.2) | 9 (4.2) | 0.001 | 0.41 (0.12–1.42) |
| 18 (7.9) | 6 (2.8) | 0.019 | 0.52 (0.11–2.4) |
| Cardiovascular diseases, n (%) | 90 (39.6) | 68 (32.1) | 0.099 | |
| 33 (14.5) | 21 (9.9) | 0.140 | |
| 34 (15.0) | 33 (15.6) | 0.864 | |
| 43 (18.9) | 9 (4.2) | 0.0001 | 0.26 (0.08–0.82) |
| 37 (16.3) | 18 (8.5) | 0.014 | 1.2 (0.45–3.35) |
| Respiratory diseases, n (%) | 56 (24.7) | 45 (21.2) | 0.392 | |
| 32 (14.1) | 36 (17.0) | 0.404 | |
| 10 (4.4) | 11 (5.2) | 0.701 | |
| Cirrhosis—chronic liver disease, n (%) | 21 (9.3) | 23 (10.8) | 0.577 | |
| Chronic kidney disease, n (%) | 35 (15.4) | 27 (12.7) | 0.420 | |
| 7 (3.1) | 6 (2.8) | 0.876 | |
| Active solid malignancy, n (%) | 10 (4.4) | 15 (7.1) | 0.152 | |
| 6 (2.6) | 15 (7.1) | 0.030 | 2.9 (0.9–8.8) |
| 4 (1.8) | 0 (0.0) | 0.090 | |
| Active hematologic disease, n (%) | 15 (6.6) | 23 (10.8) | 0.114 | |
| Neurological disease, n (%) | 30 (13.2) | 37 (17.5) | 0.217 | |
| 6 (2.6) | 11 (5.2) | 0.167 | |
| 19 (8.4) | 15 (7.1) | 0.612 | |
| 3 (1.3) | 3 (1.4) | 1.000 | |
| Immunocompromised, n (%) | 60 (26.4) | 61 (28.8) | 0.583 | |
| 45 (19.8) | 35 (16.6) | 0.381 | |
| Solid organ transplantation, n (%) | 23 (10.1) | 5 (2.4) | 0.001 | |
| HIV infection, n (%) | 4 (1.8) | 7 (3.3) | 0.302 | |
| Antibiotic therapy | ||||
| Total dose of antibiotic (mg), median (IQR) | 11,700 (6600–19,800) | 11,000 (6250–15,000) | 0.015 | |
| Duration of antibiotic therapy (days), median (IQR) | 8 (5–14) | 7 (5–10) | 0.023 | |
| Treatment regimen, n (%) | ||||
| 25 (11.0) | 115 (54.2) | 0.0001 | 0.13 (0.06–0.28) |
| 202 (89.0) | 97 (45.8) | ||
| Susceptibility-guided treatment, n (%) | 131 (57.7) | 63 (29.7) | 0.0001 | 0.35 (0.18–0.69) |
| Empirical treatment, n (%) | 96 (42.3) | 149 (70.3) | 0.104 | |
| Antibiotic prescription, n (%) | ||||
| 40 (17.6) | 75 (35.4) | 0.0001 | 0.35 (0.18–0.69) |
| 187 (82.4) | 137 (64.6) | ||
| Duration of previous antibiotic treatment (days), median (IQR) | 6 (3–10) | 3 (2–6.50) | 0.0001 | 1 (1–1) |
| Reason for switching, n (%) | ||||
| 152 (81.3) | 92 (67.2) | 0.004 | 1.3 (0.32–5.4) |
| 22 (11.8) | 39 (28.5) | 0.0001 | 6.3 (1.3–30.5) |
| 13 (7.0) | 6 (4.4) | 0.330 |
OPAT: outpatient parenteral antibiotic treatment; COPD: chronic obstructive pulmonary disease, HIV: human immunodeficiency virus, SD: standard deviation, IQR: interquartile range, p * < 0.05 = significant.
Table 2.
Infection pathways.
| Ceftaroline (Cohort N = 227) | Ceftobiprole (Cohort N = 212) | p * | |
|---|---|---|---|
| Number of infective foci, median (IQR) | 1 (1–1) | 1 (1–1) | 0.007 |
| Bloodstream infections, n (%) | 118 (51.9) | 46 (21.7) | 0.0001 |
| 31 (13.7) | 34 (16) | 0.867 |
| 27 (11.9) | 7 (3.3) | 0.0001 |
| Infective endocarditis, n (%) | 55 (24.2) | 5 (2.4) | 0.0001 |
| Respiratory tract infections, n (%) | 103 (45.4) | 140 (66) | 0.006 |
| 59 (25.9) | 65 (30.7) | 0.780 |
| 24 (10.6) | 70 (33) | 0.0001 |
| 20 (8.8) | 5 (2.4) | 0.001 |
| 27 (11.9) | 34 (16) | 0.545 |
| Soft tissue and skin infection, n (%) | 23 (10.1) | 54 (25.4) | 0.0001 |
| 4 (1.8) | 10 (4.7) | |
| 6 (2.6) | 5 (2.4) | |
| 4 (1.8) | 7 (3.3) | |
| 1 (0.4) | 20 (9.4) | |
| 2 (0.7) | 7 (3.3) | |
| 6 (2.6) | 5 (2.4) | |
| Urinary tract infection, n (%) | 6 (2.6) | 10 (4.7) | 0.277 |
| 3 (1.3) | 3 (1.4) | |
| 3 (1.3) | 5 (2.4) | |
| 0 (0.0) | 2 (0.9) | |
| Central nervous system infection, n (%) | 9 (3.9) | 8 (3.8) | 0.719 |
| 3 (1.3) | 1 (0.5) | |
| 0 (0.0) | 2 (0.9) | |
| 2 (0.7) | 3 (1.4) | |
| 4 (1.8) | 2 (0.9) | |
| Intraabdominal infection, n (%) | 10 (4.4) | 9 (4.2) | 0.724 |
| Bone and joint infection, n (%) | 13 (5.7) | 11 (5.2) | 0.580 |
| 6 (2.6) | 5 (2.4) | |
| 7 (3.1) | 1 (0.5) | |
| 0 (0.0) | 5 (2.4) | |
| Spondylodiscitis, n (%) | 9 (3.9) | 4 (1.9) | 0.133 |
| Fever without focus, n (%) | 8 (3.5) | 0 (0.0) | 0.003 |
| Other type of infection, n (%) | 6 (2.6) | 4 (1.9) | 0.468 |
UTI: urinary tract infection, p * < 0.05 = significant.
Table 3.
Microbiological isolates.
| Positive Microbial Samples | Ceftaroline (Cohort N = 150) | Ceftobiprole (Cohort N = 139) | p * |
|---|---|---|---|
| Microbial profile of isolates, n (%) | |||
| 129 (86.0) | 86 (61.9) | 0.0001 |
| 21 (14.0) | 53 (38.1) | |
| Gram-positive cocci, n (%) | 139 (92.7) | 90 (64.7) | 0.0001 |
| MR Staphylococcus aureus | 39 (26.0) | 25 (18.0) | 0.101 |
| MS Staphylococcus aureus | 31 (20.7) | 21 (15.1) | 0.219 |
| MR CoNS | 40 (26.7) | 14 (10.1) | 0.0001 |
| 31 (20.7) | 12 (8.6) | |
| 3 (2.0) | 1 (0.7) | |
| 4 (1.3) | 1 (0.7) | |
| 1 (0.7) | 0 (0.0) | |
| 1 (0.7) | 0 (0.0) | |
| MS CoNS | 9 (6.0) | 6 (4.3) | 0.519 |
| 3 (2.0) | 3 (2.2) | |
| 2 (1.3) | 1 (0.7) | |
| 0 (0.0) | 1 (0.7) | |
| 3 (2.0) | 0 (0.0) | |
| 0 (0.0) | 1 (0.7) | |
| 1 (0.7) | 1 (0.7) | |
| Enterococcus faecium | 0 (0.0) | 1 (0.7) | 0.481 |
| Enterococcus faecalis | 0 (0.0) | 10 (7.2) | 0.001 |
| Streptococcus pneumoniae | 16 (10.7) | 6 (4.3) | 0.042 |
| Other Streptococcus species | 4 (2.7) | 4 (3.6) | 0.742 |
| 1 (0.7) | 0 (0.0) | |
| 1 (0.7) | 3 (2.2) | |
| 1 (0.7) | 0 (0.0) | |
| 0 (0.0) | 1 (0.7) | |
| 1 (0.7) | 0 (0.0) | |
| Rothia spp. | 0 (0.0) | 2 (1.4) | 0.230 |
| Gram-positive bacilli, n (%) | 2 (1.3) | 1 (0.7) | 1.000 |
| 1 (0.7) | 0 (0.0) | |
| 1 (0.7) | 0 (0.0) | |
| 0 (0.0) | 1 (0.7) | |
| Gram-negative bacilli, n (%) | 9 (6.0) | 48 (19.7) | 0.0001 |
| Enterobacterales | 8 (5.3) | 12 (8.6) | 0.188 |
| 5 (3.3) | 4 (2.9) | |
| 2 (1.3) | 5 (3.6) | |
| 0 (0.0) | 1 (0.7) | |
| 0 (0.0) | 1 (0.7) | |
| 1 (0.7) | 0 (0.0) | |
| 0 (0.0) | 1 (0.7) | |
| Pseudomonas aeruginosa | 0 (0.0) | 32 (23.0) | 0.0001 |
| Other Gram-negative bacilli | 1 (0.7) | 4 (2.9) | 0.199 |
| 0 (0.0) | 2 (1.3) | |
| 0 (0.0) | 1 (0.7) | |
| 1 (0.7) | 1 (0.7) |
MR: methicillin resistant, MS: methicillin susceptible, CoNS: coagulase-negative staphylococci, p * < 0.05 = significant.
Table 4.
Outcomes.
| Ceftaroline (N = 227) | Ceftobiprole (N = 212) | p * | |
|---|---|---|---|
| Length of hospital stay (days), median (IQR) | 36 (19–60) | 19.5 (12–30.7) | 0.0001 |
| Readmission and recurrence, n (%) | |||
| 3 (1.3) | 10 (4.7) | 0.036 |
| 0 (0.0) | 3 (1.4) | 0.072 |
| Mortality, n (%) | |||
| 77 (33.9) | 45 (21.2) | 0.003 |
| 43 (18.9) | 25 (11.8) | 0.039 |
| Infection-related mortality, n (%) | |||
| 30 (13.2) | 17 (8.0) | 0.078 |
| 11 (4.8) | 7 (3.3) | 0.415 |
| 2 (0.9) | 1 (0.5) | 1.000 |
IQR: interquartile range, p * < 0.05 = significant.
Table 5.
Infective endocarditis: characteristics, antibiotic therapy, and outcomes.
| Ceftaroline (Cohort N = 55) | Ceftobiprole (Cohort N = 5) | |
|---|---|---|
| Age, mean (years) (± SD) | 69.33 (±11.62) | 67.20 (±2.39) |
| Charlson index, mean (IQR) | 5 (3–6) | 4 (4–4.50) |
| Number of infective foci, median (IQR) | 1 (1–1) | 2 (1–2) |
| Definition (modified Duke criteria), n(%) | ||
| 37 (67.3) | 1 (20) |
| 8 (14.5) | 1 (20) |
| 10 (18.2) | 3 (60) |
| Location of infective endocarditis, n (%) | ||
| 25 (45.5) | 2 (40) |
| 10 (18.2) | 0 (0.0) |
| 7 (12.7) | 1 (20) |
| 6 (10.9) | 0 (0.0) |
| 1 (1.8) | 0 (0.0) |
| Cardiac surgery, n (%) | ||
| 9 (16.4) | 0 (0.0) |
| 21 (38.2) | 1 (20) |
| 11 (20.0) | 1 (20) |
| 5 (9.0) | 0 (0.0) |
| Sepsis or septic shock, n (%) | 21 (38.2) | 3 (60) |
| Microbiological isolation, n (%) | 46 (83.6) | 5 (100.0) |
| Staphylococcus aureus | 22 (40.0) | 1 (20.0) |
| 7 (12.7) | 1 (20.0) |
| 15 (27.3) | 0 (0.0) |
| CoNS | 22 (40.0) | 1 (20.0) |
| Enterococcus faecalis | 0 (0.0) | 3 (60.0) |
| Corynebacterium coyleae | 1 (1.8) | 0 (0.0) |
| Streptococcus pneumoniae | 1 (1.8) | 0 (0.0) |
| Antibiotic combination, n (%) | 55 (100) | 5 (100) |
| 6 (10.9) | 1 (20.0) |
| 3 (5.5) | 2 (40.0) |
| 42 (76.4) | 2 (40.0) |
| Antibiotic prescription, n (%) | ||
| 7 (12.7) | 1 (20) |
| 48 (87.3) | 4 (80) |
| Reason for switching, n (%) | ||
| 36 (75.0) | 2 (50.0) |
| 8 (16.7) | 2 (50.0) |
| 4 (8.3) | 0 (0.0) |
| Total dose of antibiotic (mg), median (IQR) | 16,200 (9200–39,600) | 54,400 (7000–60,000) |
| Duration of antibiotic therapy (days), median (IQR) | 13 (6–23) | 28 (4.50–40) |
| Length of hospital stay (days), median (IQR) | 38 (20–64) | 46 (35–100) |
| Total mortality, n (%) | 22 (40) | 1 (20) |
| Related mortality, n (%) | 13 (23.6) | 1 (20) |
| 8 (14.5) | 1 (20) |
| 3 (5.5) | 0 (0.0) |
| 2 (3.6) | 0 (0.0) |
| Readmission, n (%) | 1 (1.8) | 0 (0.0) |
TAVI: transcatheter aortic valve implantation, MSSA: methicillin-susceptible Staphylococcus aureus, MRSA: methicillin-resistant Staphylococcus aureus, CoNS: coagulase-negative staphylococci, IQR: interquartile range, SD: standard deviation.
Table 6.
Adverse drug effects.
| Ceftaroline (N = 227) | Ceftobiprole (N = 212) | p * | |
|---|---|---|---|
| Total adverse effects, n (%) | 9 (4.0) | 5 (2.4) | 0.338 |
| Severity of adverse effects, n (%) | |||
| 3 (1.3) | 3 (1.4) | |
| 6 (2.6) | 2 (0.9) | |
| 0 (0.0) | 0 (0.0) | |
| 0 (0.0) | 0 (0.0) | |
| Antibiotic withdrawal for adverse effects, n (%) | 5 (2.2) | 2 (0.9) | 1.000 |
| Adverse effects by symptoms, n (%) | |||
| 2 (0.9) | 1 (0.5) | 1.000 |
| 2 (0.9) | 3 (1.4) | 0.266 |
| 1 (0.4) | 1 (0.5) | 1.000 |
| 1 (0.4) | 1 (0.5) | 1.000 |
| 1 (0.4) | 0 (0.0) | 1.000 |
| 2 (0.9) | 0 (0.0) | 0.505 |
| 2 (0.9) | 0 (0.0) | 0.505 |
p * < 0.05 = significant.
Table 7.
Bivariate and multivariate analysis of infection-related mortality.
| Deaths in Ceftaroline Group (N = 43) | Deaths in Ceftobiprole Group (N = 25) | p * | OR (95%CI) | |
|---|---|---|---|---|
| Age, mean (years) (± SD) | 65.84 (±10.50) | 75.88 (±13.64) | 0.001 | 0.9 (0.81–1.2) |
| Charlson index, median (IQR) | 5 (4–7) | 4 (4–6.50) | 0.330 | |
| Men, n (%) | 29 (67.4) | 17 (68.0) | 0.962 | |
| Sepsis | 25 (58.1) | 14 (56.0) | 0.863 | |
| Septic shock | 19 (44.2) | 7 (28.0) | 0.185 | |
| Infection acquisition, n (%) | ||||
| Community acquired | 15 (34.9) | 11 (44.0) | 0.456 | |
| Nosocomial/Nosohusial | 28 (65.1) | 14 (56.0) | ||
| Inpatient department, n (%) | ||||
| Medical department | 40 (93.0) | 22 (88.0) | 0.481 | |
| Surgical department | 3 (7.0) | 2 (8.0) | 0.876 | |
| OPAT, n (%) | 0 (0.0) | 1 (4.0) | 0.186 | |
| Comorbidities, n (%) | ||||
| Cardiovascular risk factors | 36 (83.7) | 19 (76.0) | 0.435 | |
| Obesity | 8 (18.6) | 0 (0.0) | 0.022 | 0 (0–0) |
| Cardiovascular diseases | 23 (53.5) | 6 (24.0) | 0.018 | 3.1 (0.2–69) |
| Ischemic heart disease | 11 (25.6) | 1 (4.0) | 0.024 | 0.15 (0.001–27) |
| Moderate-severe valve disease | 12 (27.9) | 0 (0.0) | 0.004 | 0 (0–0) |
| Respiratory diseases | 13 (30.2) | 6 (24.0) | 0.581 | |
| Cirrhosis—chronic liver disease | 3 (7.0) | 2 (8.0) | 1.000 | |
| Chronic kidney disease | 10 (23.3) | 3 (12.0) | 0.255 | |
| Active solid malignancy | 4 (9.3) | 2 (8.0) | 1.000 | |
| Active hematologic disease | 3 (7.0) | 3 (12.0) | 0.481 | |
| Neurological disease | 7 (16.3) | 7 (28.0) | 0.249 | |
| Immunocompromised patients | 16 (37.2) | 10 (40.0) | 0.819 | |
| Infection pathways, n (%) | ||||
| Bloodstream infections | 24 (54.5) | 5 (17.2) | 0.001 | 0.09 (0.004–2.7) |
| Infective endocarditis | 13 (29.5) | 1 (3.4) | 0.006 | 8.6 (0.35–210) |
| Community-acquired pneumonia | 6 (13.6) | 12 (41.4) | 0.007 | 0 (0–0) |
| Nosocomial pneumonia | 5 (11.4) | 9 (31.0) | 0.037 | |
| Ventilator-associated pneumonia | 9 (20.5) | 3 (10.3) | 0.254 | |
| Coinfection with SARS-CoV-2 | 6 (13.6) | 8 (27.6) | 0.139 | |
| Fungal coinfection | 5 (11.4) | 0 (0.0) | 0.150 | |
| Soft tissue and skin infection | 2 (4.5) | 3 (10.3) | 0.380 | |
| Intraabdominal infection | 3 (6.8) | 1 (3.4) | 0.925 | |
| Central nervous system infection | 1 (2.3) | 0 (0.0) | 1.000 | |
| Bone and joint infection | 1 (2.3) | 1 (3.4) | 1.000 | |
| Spondylodiscitis | 3 (6.8) | 0 (0.0) | 0.272 | |
| Microbiological isolates, n (%) | ||||
| General microbial profile | ||||
| 20 (45.5) | 15 (51.7) | 0.600 | |
| 24 (54.5) | 14 (48.3) | ||
| Microbial profile of isolates | ||||
| 22 (91.7) | 7 (50.0) | 0.004 | 2.6 (0.01–644) |
| 2 (8.3) | 7 (50.0) | ||
| Gram-positive cocci | ||||
| 5 (20.8) | 5 (35.7) | 0.315 | |
| 9 (37.5) | 2 (14.3) | 0.128 | |
| 6 (25.0) | 0 (0.0) | 0.067 | |
| 2 (8.3) | 0 (0.0) | 0.522 | |
| 0 (0.0) | 2 (14.3) | 0.129 | |
| 2 (8.3) | (0.0) | 0.522 | |
| Gram-negative bacilli | 0 (0.0) | 5 (35.7) | 0.004 | |
| Pseudomonas aeruginosa | 0 (0.0) | 5 (35.7) | 0.002 | |
| Antibiotic therapy | ||||
| Total dose (mg), median (IQR) | 9600 (5400–14,400) | 9000 (5000–12,500) | 0.545 | |
| Duration of antibiotic therapy (days), median (IQR) | 7 (3–12) | 6 (3–8.50) | 0.527 | |
| Antibiotic prescription, n (%) | ||||
| 4 (9.3) | 6 (24.0) | 0.099 | 2.6 (0.02–391) |
| 39 (90.7) | 19 (76.0) | ||
| Treatment regimen, n (%) | ||||
| 3 (7.0) | 17 (56.0) | 0.0001 | 0 (0–0) |
| 40 (93.0) | 12 (44.0) | ||
| Empirical treatment, n (%) | 20 (46.5) | 21 (84.0) | 0.002 | 0.3 (0.01–6.7) |
MRSA: methicillin-resistant Staphylococcus aureus, MSSA: methicillin-susceptible S. aureus, MR CoNS: methicillin-resistant coagulase-negative staphylococci, MS CoNS: methicillin-susceptible coagulase-negative staphylococci, OPAT: outpatient parenteral antibiotic therapy, SD: standard deviation, IQR: interquartile range, p * < 0.05 = significant.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
MDPI and ACS Style
Arnés García, D.; Pitto-Robles, I.; Calderón Parra, J.; Calvo Salvador, M.; Herrero Rodríguez, C.; Gisbert, L.; Hidalgo-Tenorio, C. Ceft-to-Ceft Study: Real-Life Experience with Ceftaroline and Ceftobiprole in Treatment of the Principal Infectious Syndromes in a Spanish Multicenter Hospital Cohort. Antibiotics 2023, 12, 1692. https://doi.org/10.3390/antibiotics12121692
AMA Style
Arnés García D, Pitto-Robles I, Calderón Parra J, Calvo Salvador M, Herrero Rodríguez C, Gisbert L, Hidalgo-Tenorio C. Ceft-to-Ceft Study: Real-Life Experience with Ceftaroline and Ceftobiprole in Treatment of the Principal Infectious Syndromes in a Spanish Multicenter Hospital Cohort. Antibiotics. 2023; 12(12):1692. https://doi.org/10.3390/antibiotics12121692
Chicago/Turabian StyleArnés García, Daniel, Inés Pitto-Robles, Jorge Calderón Parra, Marina Calvo Salvador, Carmen Herrero Rodríguez, Laura Gisbert, and Carmen Hidalgo-Tenorio. 2023. "Ceft-to-Ceft Study: Real-Life Experience with Ceftaroline and Ceftobiprole in Treatment of the Principal Infectious Syndromes in a Spanish Multicenter Hospital Cohort" Antibiotics 12, no. 12: 1692. https://doi.org/10.3390/antibiotics12121692
Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.
