Attainment of Target Antibiotic Levels by Oral Treatment of Left-Sided Infective Endocarditis: A POET Substudy

Abstract

Background In the POET (Partial Oral Endocarditis Treatment) trial, oral step-down therapy was noninferior to full-length intravenous antibiotic administration. The aim of the present study was to perform pharmacokinetic/pharmacodynamic analyses for oral treatments of infective endocarditis to assess the probabilities of target attainment (PTAs). Methods Plasma concentrations of oral antibiotics were measured at day 1 and 5. Minimal inhibitory concentrations (MICs) were determined for the bacteria causing infective endocarditis (streptococci, staphylococci, or enterococci). Pharmacokinetic/pharmacodynamic targets were predefined according to literature using time above MIC or the ratio of area under the curve to MIC. Population pharmacokinetic modeling and pharmacokinetic/pharmacodynamic analyses were done for amoxicillin, dicloxacillin, linezolid, moxifloxacin, and rifampicin, and PTAs were calculated. Results A total of 236 patients participated in this POET substudy. For amoxicillin and linezolid, the PTAs were 88%-100%. For moxifloxacin and rifampicin, the PTAs were 71%-100%. Using a clinical breakpoint for staphylococci, the PTAs for dicloxacillin were 9%-17%. Seventy-four patients at day 1 and 65 patients at day 5 had available pharmacokinetic and MIC data for two oral antibiotics. Of those, 13 patients at day 1 and 14 patients at day 5 did only reach the target for one antibiotic. One patient did not reach target for any of the two antibiotics. Conclusion For the individual orally administered antibiotic, the majority of patients reached the target level. Patients with sub-target levels were compensated by the administration of two different antibiotics. The findings support the efficacy of oral step-down antibiotic treatment in patients with infective endocarditis.

Oral Antibiotics for Bacteremia and Infective Endocarditis: Current Evidence and Future Perspectives

“…Another drug class that should be used with extreme caution against S. aureus endocarditis is oral betalactams. This conclusion is derived from a PK/PD study based on TDM results from POET trial, where using a clinical breakpoint for staphylococci, the PTA for dicloxacillin was 9%-17% [159]. A schematic illustration of the current antibiotic armamentarium depending on blood culture result is provided in Figure 1.…”

Using antibiotics wisely

“…A 3-year [40] and 5-year follow-up study of the POET trial [41 ▪ ] also demonstrated there were no clinically significance differences in incidences of cardiac surgery, embolic events, or relapse of infection; but PO stepdown group actually had a lower incidence of overall mortality (23.4% vs 35.2%; hazard ratio, 0.61; CI, 0.42 to 0.88) [41 ▪ ]. The POET study also evaluated the Pharmacokinetic and Pharmacodynamic (PK/PD) findings of the oral antibiotics in the study measuring the antibiotic serum levels sequentially while on therapy [42 ▪ ]. They were determining if the oral antibiotic levels reached target attainment above the minimal inhibitory concentrations (MIC) of the organisms being treated.…”

“…Less than half of the oral antibiotics used reached levels to treat the infections based on their MIC, most likely due to rifampin decreasing the levels of moxifloxacin and linezolid, however there was no impact on outcomes. This suggests that once the IV component has cleared the blood, the role of PO therapy is to reduce relapse of infection [42 ▪ ]. A real world example of the impact of IV-PO step-down therapy for IE was performed at three acute care hospitals [25 ▪▪ ].…”

Ten common misconceptions about antibiotic use in the hospital

“…15 Contemporary literature reviewing the administration of oral versus parenteral therapy for select cases of osteomyelitis, infective endocarditis, and bacteremia has confirmed the usage of oral therapies to be effective if optimal doses can be clinically achieved. [16][17][18] Additionally, the usage of oral therapies obviates the risk of phlebitis, thrombosis, and line-associated bloodstream T A B L E 1 Antimicrobials with high oral bioavailability. 14…”