Binding of temocillin to plasma proteins in vitro and in vivo: the importance of plasma protein levels in different populations and of co-medications.

BACKGROUND: Temocillin plasma protein binding (PPB) in healthy individuals is reported to be ∼85% but had not been studied in patients. OBJECTIVES: To obtain normative data on temocillin PPB in patients in relation to infection and impact of co-medications widely used in ICU. METHODS: Plasma was obtained from healthy individuals (Group #1), non-ICU patients with UTI (Group #2), ICU patients with suspected/confirmed ventriculitis (Group #3) or with sepsis/septic shock (Group #4). Total and unbound temocillin concentrations were measured in spiked samples from temocillin-naive donors (in vitro) or in plasma from temocillin-treated subjects (in vivo). The impact of diluting plasma, using pharmaceutical albumin, or adding drugs potentially competing for PPB was tested in spiked samples. Data were analysed using a modified Hill-Langmuir equation taking ligand depletion into account. RESULTS: Temocillin PPB was saturable in all groups, both in vitro and in vivo. Maximal binding capacity (Bmax) was 1.2-2-fold lower in patients. At 20 and 200 mg/L (total concentrations), the unbound fraction reached 12%-29%, 23%-42% and 32%-52% in Groups #2, #3, #4. The unbound fraction was inversely correlated with albumin and C-reactive protein concentrations. Binding to albumin was 2-3-fold lower than in plasma and non-saturable. Drugs with high PPB but active at lower molar concentrations than temocillin caused minimal displacement, while fluconazole (low PPB but similar plasma concentrations to temocillin) increased up to 2-fold its unbound fraction. CONCLUSIONS: Temocillin PPB is saturable, 2-4-fold lowered in infected patients in relation to disease severity (ICU admission, hypoalbuminaemia, inflammation) and only partially reproducible with albumin. Competition with other drugs must be considered for therapeutic concentrations to be meaningful.

Rat bite fever: a case report review.

CONTEXT: Rat bite fever is a rare disease with a challenging differential diagnosis. The zoonosis has a potentially lethal course in a vulnerable population (children and low socioeconomic class) and a commonly available standard therapy (penicillin). This case report review outlines common epidemiological and clinical factors to improve clinical awareness and timely response to therapeutic actions. METHODS: A systematic literature review was conducted in the PubMed database looking for English language European case reports of rat bite fever from 2000 to 2021. RESULTS: In 17 out of 20 selected cases, the condition of the index patient was identified as an infectious syndrome. Thanks to the almost omnisensitive susceptibility pattern of Streptobacillus moniliformis, timely antibiotic administration prevented an unfavorable outcome in all these cases. However, in the three remaining cases, the initial diagnoses were arthritis (on autoimmune basis and gout) and viral syndrome. Due to delayed antibiotic administration, one case suffered persistent harm, while the other two cases encountered prolonged illness. CONCLUSION AND RECOMMENDATIONS: Rat bite fever is a diagnosis that can be easily missed from both a clinical and a microbiological point of view. As such, rat bite fever becomes part of the differential diagnosis whenever a patient presents with a fever syndrome after being in contact with rodents. In the case of persistent fever, blood culture sampling should be performed even in the absence of a systemic inflammatory response. A bacterial 16S ribosomal RNA PCR on blood or joint aspiration (cultures) is an even more sensitive diagnostic test. Since most transmissions occurred in a domestic setting, keeping rats as pets cannot be recommended.