In vivo interactions of continuous flucloxacillin infusion and high-dose oral rifampicin in the serum of 15 patients with bone and soft tissue infections due to Staphylococcus aureus - a methodological and pilot study

Abstract

BackgroundIncreased antibiotic resistance against Staphylococcus aureus and low penetration into bone requires regimen optimization of available drugs.MethodsWe evaluate pharmoacokinetic and pharmacodynamic parameters (PK/PD) as well as in vivo interactions of continuous flucloxacillin 12 g/d administration combined with high dose oral rifampicin 600 mg bid in the serum of 15 adult patients with bone and soft tissue infections. We use the patient’s own serum directed against his own isolated S. aureus strain to reproduce in vivo conditions as closely as possible.ResultsThe continuous flucloxacillin infusion constantly generated plasma free drug levels largely exceeding the serum minimal inhibitory concentrations (mean 74-fold). Combination with rifampicin significantly increased flucloxacillin levels by 44.5%. Such an increase following rifampicin introduction was documented in 10/15 patients, whereas a decrease was observed in 1/15 patients. Finally, all infections were cured and the combination was well tolerated.ConclusionsIn this in vivo methodological pilot study among adult patients with orthopaedic infections due to S. aureus, we describe a new method and reveal substantial but inconsistent interactions between flucloxacillin and rifampicin, of which the clinical significance remains unclear.

Prosthetic Joint Infections Due to Coagulase-Negative Staphylococci

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Paclitaxel, Imatinib and 5-Fluorouracil Increase the Unbound Fraction of Flucloxacillin In Vitro

“…For instance, a decrease in the international normalized ratio was shown in several reports after FLU was added to warfarin therapy, probably caused by an induction of the hepatic CYP3A4 isoenzyme [42]. Further interactions with piperacillin [42,43], voriconazole [44,45], rifampicin [46], quinolones [47] and paracetamol [48] have been shown in different studies.…”

Oral Flucloxacillin for Treating Osteomyelitis: A Narrative Review of Clinical Practice

“…In a study in 15 adult patients with various osteoarticular infections (55) the combined treatment with intravenous FLU and oral rifampicin significantly increased serum FLU levels by 45% in 10 patients, while a decrease was observed in one patient. The clinical significance of this finding remained unknown, since all infections were cured (55). It is likely that oral FLU could also be associated with such an interaction, although possibly at a subclinical level.…”