Collection of Data of Ceftobiprole Treated Patients: Comparison of Patients With and Without Certain Diseases

Rationale and background:

Ceftobiprole is a beta-lactam antibiotic with bactericidal activity against a broad spectrum of Gram-positive and Gram-negative bacteria, that was developed to treat patients with pneumonia both in a hospital or community setting. Clinical trials were conducted in adult immune-competent patients with normal or mild to moderate renal or hepatic function impairment. The clinical trial program completed to date has excluded patients with immune suppression and significant organ function impairment (hepatic or renal). The safety profile of ceftobiprole in these patient groups was recognized during the marketing authorization procedure as important missing information and the applicant committed to conduct a post authorization safety study.

A randomized Phase 3 study in the indication of acute bacterial skin and skin structure infections (ABSSSIs) is completed (NCT03137173), and a randomized Phase 3 study in the indication of S. aureus bacteremia is ongoing (NCT03138733). This retrospective chart review is conducted to further evaluate the safety profile of ceftobiprole in patient populations with specific risk factors.

Research question:

To estimate the proportion and the relative frequency of treatment-emergent adverse events (AEs) and adverse event of special interest will be assessed in patients treated with ceftobiprole and who have at least one of the following conditions:

• Impaired renal function
• Impaired hepatic function
• Immunosuppression

Treatment-emergent AEs are defined as events occurring after first study-drug administration, up to 28 days after the completion of treatment.

Adverse Events of Special Interest are the following;

• Hyponatraemia
• Hepatobiliary disorders
• Renal toxicity (including potential interactions with nephrotoxic drugs)
• Coombs test (DAT) positivity + clinical evidence of haemolysis
• Hypersensitivity reactions, including anaphylactic reactions
• Pseudomembranous colitis / C. difficile colitis
• Convulsions

The observed frequency of adverse events and adverse events of special interest in patients with the above risk factors will be compared to the frequency of these adverse events and adverse events of special interest in patients without these risk factors.

The study will enroll patients in whom treatment with ceftobiprole has been completed.

Patient charts will be selected from hospital sentinel sites.

Patient observation would normally be planned for 28 days after completion of ceftobiprole therapy. If, at the time of the review of any patient medical records, an AE has not been resolved, these patients would be followed up until resolution.

The study would continue until the target number of patients has been reached. The end date of this study would be set at the date of the last patient record review, or in cases where follow-up is extended beyond this period, until the end of follow-up.

Variables:

The following variables will be identified from the patient charts

• Year of birth and gender
• Weight
• Indication of treatment
• Attribution to a specific population group (see inclusion criteria) and criteria to assign the patient
• Start date of ceftobiprole
• Stop date of ceftobiprole and main reason for stopping (if known)
• Prescribed dose/regimen at treatment start
• Changes in dose during treatment
• Relevant medical history (diagnosis within 1 year prior to treatment start)
• Presence of ascites and hepatic encephalopathy at baseline
• Laboratory investigations undertaken as part of routine clinical practice and management of the patient related to the outcomes of interest, e.g., serum sodium, AST (aspartate aminotransferase), ALT (alanine aminotransferase), serum albumin, total bilirubin, GGT (gamma-glutamyltransferase) and AP (alkaline phosphatase), prothrombin time, INR (international normalized ratio), creatinine, haemoglobin, HCT (hematocrit), Coombs (DAT), C. difficile toxin tests prior (within 1 month) and up to 28 days after completion of treatment
• Findings of colonoscopy/sigmoidoscopy (for C. difficile colitis)
• Concomitant medication at baseline and up to 28 days after completion of treatment with focus on new onset use or dose modification of medications to treat hypersensitivity/anaphylaxis, convulsions, or C. difficile colitis
• Treatment-emergent AEs (event reports up to 28 days after completion of treatment), with focus on AEs of special interest (AESIs)
• Date and cause(s) of death (if applicable)
• Use during pregnancy (with follow-up until delivery)

Data sources:

This study will use data from patient charts, which includes physician and nurse notes, admission and discharge summaries, consultancy reports, laboratory test sheets, and microbiology sheets.

The study will enroll participants in whom treatment with ceftobiprole has been completed (including both on-label and off-label use) plus at least one of the following criteria (more than one criterion may apply):

• Participants with severe renal impairment / ESRD (end-stage renal disease, defined as calculated CLCr ( creatinine clearance) < 30 mL/minute or oliguria < 20 mL/hour unresponsive to fluid challenge or any form of dialysis)
• Impaired baseline hepatic function (patients with liver failure/cirrhosis Child Pugh Grade A, B, C or existing non-cirrhotic liver disease associated with total bilirubin > 2 mg/dL or alanine aminotransferase [ALT], or aspartate aminotransferase [AST] ≥ 3 times upper limit of the normal range [ULN])
• Participants with immunosuppression, i.e.,

• HIV-positive with CD4 (cluster of differentiation 4) counts of ≤ 0.2 × 10E9/L (≤ 200 cells/mm3)
• Immunocompromised as determined by the investigator (any type or aetiology)
• Baseline neutropenia or baseline myelosuppression, defined as presence of myelosuppression or neutropenia (absolute neutrophil count [ANC] ≤ 0.5 × 10E9/L [< 500 polymorphonuclear neutrophils (PMNs)/mm3]), severe anaemia (haemoglobin < 6.5 g/dL), or severe thrombocytopenia (< 49.9 × 10E9/mm3) In addition, the study will enroll a control group of patients in whom treatment has been completed without any of the criteria listed above.