Abstract
Treatment failure in biofilm-associated bacterial infections is an important healthcare issue. In vitro studies and mouse models suggest that bacteria enter a slow-growing/non-growing state that results in transient tolerance to antibiotics in the absence of a specific resistance mechanism. However, little clinical confirmation of antibiotic tolerant bacteria in patients exists. In this study we investigate a Staphylococcus epidermidis pacemaker-associated endocarditis, in a patient who developed a break-through bacteremia despite taking antibiotics to which the S. epidermidis isolate is fully susceptible in vitro. Characterization of the clinical S. epidermidis isolates reveals in-host evolution over the 16-week infection period, resulting in increased antibiotic tolerance of the entire population due to a prolonged lag time until growth resumption and a reduced growth rate. Furthermore, we observe adaptation towards an increased biofilm formation capacity and genetic diversification of the S. epidermidis isolates within the patient.
Highlights
Treatment failure in biofilm-associated bacterial infections is an important healthcare issue
The leads of the first inactive pacemaker were left in situ since they could not be removed without causing damage and were cut and capped
We show in-host evolution of a ST378 S. epidermidis strain, of which multiple spatially and temporally distinct isolates were recovered from a patient with a biofilm-associated pacemaker endocarditis
Summary
Treatment failure in biofilm-associated bacterial infections is an important healthcare issue. The environment within a biofilm is heterogeneous, with nutrient limitation in the lower layers restricting growth These non-growing or slow-growing bacteria are protected from antibiotics targeting active cell growth While the antibiotic minimum inhibitory concentration (MIC) is the gold-standard metric to assess resistance, the minimum duration to killing (MDK) metric has been proposed to define tolerance[2] The longer it takes to kill the bulk of a bacterial population, the more tolerant this population is. The phenotypic tolerance is a transient state induced by a specific environment, such as low pH, nutrient limitation, or antibiotic challenge[5]. It often characterizes only a fraction of the population, referred to as persister cells. Bacterial tolerance is still mainly restricted to the endpoint observations of antibiotic treatment failures caused by antibiotic-susceptible bacteria[9]
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