Real-life use of ceftobiprole for severe infections in a French intensive care unit

Real-life use of ceftobiprole for severe infections in a French intensive care unit

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Introduction

(Article introduction authored by ICU Editorial Team)

This study retrospectively analyzed the use of Ceftobiprole (CBP), an anti-MRSA cephalosporin, in treating severe infections in critically ill patients with multiple infected sites.

The research spanned from January 2016 to December 2021 in a single intensive care unit (ICU). Among 47 patients treated with CBP, pneumonia was the predominant indication (51%), often accompanied by bacteremia (72%).

Polymicrobial infections were observed in all cases. Approximately 80% of patients achieved clinical cure, with 32% in-hospital mortality. Only five patients developed new carriage of multidrug-resistant (MDR) bacteria.

Trough CBP concentrations were monitored in 16 patients. Notably, 33% of Enterobacterales strains showed resistance to CBP based on EUCAST 2023 clinical breakpoints, emphasizing the importance of monitoring concentrations, especially in cases with high minimum inhibitory concentration (MIC).

Methods:

          Inclusion Criteria:

  • All ICU patients treated with Ceftobiprole (CBP) for documented infections were included.
  • Regardless of infection site or severity during treatment.
  • Patients with documented primitive bacteremia were included.

    Data Collection:

• Monocentric observational study in a medical and surgical ICU at Versailles Hospital Center.

  • Anonymized data collected in a local database on the secure hospital network.
  • Patient demographics, Simplified Acute Physiology Score II (SAPS II), and immunocompromised status recorded.
  • Data collected retrospectively from January 2016 to December 2021 using hospital software.
  • Empiric antibiotic therapy details, sites of infection, bacteremia presence, and CBP trough concentrations recorded.
  • Infections defined for pneumonia, hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), urinary tract infections, and intra-abdominal infections.


    Microbiology and Pharmacology:

    • Bacterial identification using mass spectrometry, antimicrobial susceptibility testing (AST) by disk diffusion.

    • CBP minimum inhibitory concentrations (MICs) determined using predefined antibiotic concentration gradients.

    • AST results interpreted based on guidelines from Comité de l’Antibiogramme de la Société Française de Microbiologie – European Committee on Antimicrobial Susceptibility Testing (CASFM-EUCAST).

    • Trough CBP assays performed when clinically relevant.

    • Outcome assessed through clinical cure, defined as regression of signs and inflammatory syndrome after CBP treatment.

    • Secondary endpoints included in-hospital mortality and documentation of multidrug-resistant (MDR) pathogen carriage.

    Statistical Analysis and Ethical Considerations:

  • Descriptive statistical analysis presented as percentages for categorical variables and medians (interquartile range) for continuous variables.
  • Ethical approval obtained from the Commission d’Ethique de la Société de Réanimation de Langue Française.
  • Compliance with French legislation on noninterventional studies, following reference methodology MR-004 supervised by the DRCI of the Versailles Hospital Center, including secure local storage and data anonymization.

Results

Patients

Between January 2016 and December 2021, a total of 55 patients received Ceftobiprole (CBP). Eight patients were excluded for receiving CBP empirically, leaving 47 patients included in the study who received CBP after microbiological documentation.

The primary indication for CBP treatment was pneumonia in 51% of cases, often accompanied by associated bacteremia in 72% of patients. Seven individuals faced severe acute renal failure, two of whom required renal replacement therapy.

Most patients exhibited glomerular clearance exceeding 30 ml/min. These demographic and clinical characteristics offer insights into the real-world use of CBP in treating microbiologically documented infections, particularly in cases involving pneumonia and bacteremia.

All in all, the MICs of 29 Gram-negative bacteria strains were available, including 21 for Enterobacterales and eight for Pseudomonas aeruginosa (Table 4 and details: Table S1 in the appendix).

Out of the 21 strains of Enterobacterales, 33% were considered to be resistant to CBP based on MIC > 0.25 mg/L (CASFM-EUCAST Breakpoint[17]) but the patients still received CBP treatment.

The proportion of clinical cure was similar whether the MIC was greater (resistant) or less than 0.25 mg/L.

Only one Pseudomonas aeruginosa strain tested (n = 8) was resistant to CBP, with a MIC > 8 mg/L.

Microbiology and antibiotics

Prior to microbiological documentation, almost all patients in the study received empiric antibiotic therapy, with a 50% incidence of combination therapy.

The specific antibiotics administered before Ceftobiprole (CBP) treatment with a median duration of two days for prior antibiotic therapy.

Microbiological documentation revealed that all infections were polymicrobial. Expressing the proportion of Enterobacteriaceae is challenging due to the potential for a single patient to be infected with multiple species of Enterobacterales.

This highlights the complexity and diversity of microbial profiles in the context of severe infections treated with CBP.

Use of ceftobiprole and outcome

The dosage regimens of Ceftobiprole (CBP) are outlined in Table 5. Trough blood concentrations of CBP were determined for 34% of patients after a median of six intravenous injections, indicating a steady state.

Heterogeneous trough concentrations were observed across different doses (Fig. 1). Modification of CBP dosage occurred in only three cases based on residual blood concentration results.

The median duration of CBP treatment was seven days, with nearly 25% of cases involving combination therapy, primarily with fluoroquinolone metronidazole. Some patients received dual antibiotic therapy alongside CBP.

Clinical cure was achieved in over 80% of patients, with treatment failures indicated by persistent infection signs. Secondary endpoints revealed only four patients with new carriage of a multidrug-resistant (MDR) pathogen, and in-hospital mortality stood at 32%

These findings shed light on CBP dosing variability, treatment duration, and outcomes in the context of severe infections.

Clinical failure

Among the 10 patients with clinical treatment failure, four were treated for nosocomial pneumonia, including ventilator-associated pneumonia (VAP).

In one VAP case, multiple strains of Pseudomonas aeruginosa remained resistant to Ceftobiprole (CBP) after seven days of treatment, while another case showed new resistance after 48 hours.

Two VAP failures were linked to persistent symptoms and new positive respiratory samples with Enterobacteriaceae, theoretically sensitive to CBP.

Three failures involved intra-abdominal infections, including carbapenem use due to CBP resistance in Hafnia alvei-related peritonitis. Other cases included a fatal hepatic abscess and superinfected hematoma, with one patient’s treatment lasting 25 days.

Notably, a clinical failure occurred in Pseudomonas aeruginosa and Enterococcus faecalis bacteremia without identified primary infection, with P. aeruginosa sensitivity confirmed by a new antibiogram.

These diverse failure scenarios underscore the challenges in treating severe infections and the importance of understanding resistance patterns.

Discussion

This monocentric observational retrospective cohort study of 47 critically ill patients in an intensive care unit (ICU) reports on the real-life use of Ceftobiprole (CBP) for severe infections.

Clinical cure was achieved in 79% of cases, and microbiological data revealed polymicrobial infections in all cases. Despite CBP being mainly used for pneumonia, particularly ventilator-associated pneumonia (VAP), with associated bacteremia, clinical efficacy appeared acceptable.

However, CBP was used for various infections beyond respiratory or skin issues, with 10 observed treatment failures. The study notes variability in trough CBP concentrations and the need for patient-specific adaptations based on blood concentration measurements.

While CBP demonstrated efficacy in this cohort, the study emphasizes the necessity for further research on its effectiveness, ecological impact, and cost-effectiveness before considering broader applications in severe polymicrobial infections among critically ill patients.

Source: Bellut, Hugo, et al. “Real-life use of ceftobiprole for severe infections in a French intensive care unit.” Infectious Diseases Now 54.1 (2024): 104790.