Distinct Effectiveness of Oritavancin Against Tolerance-Induced

antibiotics Communication Distinct Effectiveness of Oritavancin against Tolerance-Induced Staphylococcus aureus Andrew D. Berti 1,2,* , Lauren T. Harven 1 and Victoria Bingley 1 1 Department of Pharmacy Practice, Wayne State University College of Pharmacy and Health Sciences, Detroit, MI 48201, USA; [email protected] (L.T.H.); [email protected] (V.B.) 2 Department of Biochemistry, Microbiology and Immunology, Wayne State University College of Medicine, Detroit, MI 48201, USA * Correspondence: [email protected]; Tel.: +1-313-577-3565 Received: 20 October 2020; Accepted: 6 November 2020; Published: 8 November 2020 Abstract: Within a sufficiently large bacterial population, some members will naturally adopt an alternate, metabolically-active state that favors small molecule synthesis over cell division. These isogenic “tolerant” subpopulations have variable responses during antibiotic exposure and can remain viable in the presence of typically bactericidal concentrations. In this study, we determine the ability of typical and atypical antistaphylococcal therapies to reduce the viability of mupirocin-induced tolerant Staphylococcus aureus bacteria. Overall, tolerance-induced staphylococci exhibited a markedly decreased rate and extent of killing following antibiotic exposure. However, oritavancin remained effective at maintaining a similar extent of killing. Further studies to investigate the role of oritavancin against recurrent or relapse staphylococcal infection are warranted. Keywords: MRSA; oritavancin; tolerance; persistence; lipoglycopeptide 1. Introduction Staphylococcus aureus is the most common invasive human pathogen and remains a major contributor to infection-related morbidity and mortality [1]. Clinicians have long recognized the role of antibiotic resistance in treatment failures [2]. Over the past decade, it has become clear that antibiotic tolerance can also contribute to unfavorable clinical outcomes [3]. Antimicrobial tolerance occurs when a small fraction of a bacterial population ceases to focus on cell division and shifts to an alternate metabolic program favoring small molecule synthesis over growth [4,5]. In S. aureus, this process can be sharply accelerated by multiple factors present during infection including nutrient limitation, host cationic peptide exposure and polymorphonuclear neutrophil internalization [6,7]. Antimicrobial agents in clinical use are typically most effective against rapidly dividing bacteria, allowing this isogenic subpopulation to survive in otherwise bactericidal concentrations. Survivors of the antibiotic exposure can restart cell division upon cessation of antibiotics and cause relapse or recurrent infection. In this study we determine the ability of typical and atypical antistaphylococcal therapies to reduce the viability of tolerant Staphylococcus aureus bacteria. At the turn of the millennium, vancomycin (VAN) was considered the “antibiotic of last resort” for treatment of methicillin-resistant Staphylococcus aureus (MRSA) infection. Since then several antimicrobial agents with anti-MRSA activity have been introduced into clinical practice including daptomycin (DAP), telavancin (TLV),ceftaroline (CPT), dalbavancin (DAL) and oritavancin (ORI). While vancomycin remains the mainstay of contemporary anti-MRSA pharmacotherapy, each of the newer agents has seen use in bloodstream infections, particularly those that do not respond appropriately to vancomycin. Because of their “second-line” clinical utilization, it becomes important to assess how these newer agents perform against antibiotic-tolerant staphylococci. Historically, the infrequent Antibiotics 2020, 9, 789; doi:10.3390/antibiotics9110789 www.mdpi.com/journal/antibiotics Antibiotics 2020, 9, 789 2 of 7 Antibiotics 2020, 9, x FOR PEER REVIEW 2 of 7 infrequentand stochastic and stochastic behavior behavior of antimicrobial of antimicrobial tolerance tolerance has limited has evaluationlimited evalua of antimicrobialstion of antimicrobials against againstantibiotic-tolerant antibiotic-tolerant subpopulations. subpopulations. However, However, with the findingwith the that finding mupirocin that mupirocin exposure can exposure synchronize can synchronizean entire population an entire population into a tolerant into statea tolerant [8,9], state we now [8,9], have we now the capacity have the to capacity specifically to specifically assess the assesscapability the capability of antimicrobials of antimicrobials to reduce viability to reduce of vi tolerantability bacteria.of tolerant Therefore, bacteria. our Therefore, primary our experimental primary experimentalendpoint is sustained endpoint bactericidal is sustained activity bactericidal of an antibiotic activity of over an 48antibiotic h against over a culture 48 h against synchronized a culture to a synchronizedtolerant state to by a high-dose tolerant stat mupirocine by high-dose exposure. mupirocin Our secondary exposure. endpoint Our secondary is the minimal endpoint duration is the of minimalexposure duration sufficient of toexposure reduce viabilitysufficient by to 99.9% reduce (MDK). viability by 99.9% (MDK). 2.2. Results Results AsAs expected, expected, VAN, VAN, CPT, CPT, DAL, DAL, TLV, TLV, DAP DAP and and ORI ORI reduced reduced the the viability viability of of traditional traditional bacterial bacterial cultures,cultures, frequently frequently achieving achieving bactericidal bactericidal activity activity within within 48 48 h h (Figure (Figure 11).). At At a low mupirocin concentration,concentration, statistically-significant statistically-significant prolongations prolongations were were observed observed in in the the MDK MDK for for VAN, VAN, CPT, CPT, DAL, DAL, TLVTLV and and DAP DAP although although bactericidal bactericidal activity activity in in general general was was maintained. maintained. The The exception exception to to this this trend trend waswas ORI whichwhich demonstrateddemonstrated no no significant significant MDK MDK prolongation prolongation (Table (Table1). At high1). At mupirocin high mupirocin exposure, exposure,pronounced pronounced prolongations prolongations were again were observed again in observed the MDK, in e fftheectively MDK, eliminating effectively theeliminating 48 h bactericidal the 48 hactivity bactericidal of DAP activity against of three DAP isolates against and three of DAL,isolat TLV,CPTes and of andDAL, VAN TLV, against CPT alland five VAN isolates. against In contrast,all five isolates.ORI was In the contrast, only agent ORI was to meet the only our primaryagent to endpointmeet our andprimary maintain endpoint bactericidal and maintain activity bactericidal against all activityisolates against at maximal all isolates induction at maximal of tolerance. induction We doof tolerance. note, however, We do the note, biphasic however, kill kinetics the biphasic with kill ORI kineticsresulting with in aORI prolonged resulting MDK in a forprolonged two of theMDK isolates for two (Table of the2). isolates (Table 2). FigureFigure 1. ActivityActivity ofof study study antibiotics antibiotics against against mupirocin-induced mupirocin-induced tolerant tolerant staphylococci. staphylococci. Data represent Data representthe mean the and mean standard and deviation standard values deviation from fivevalues distinct from strains, five distinct each evaluated strains, ineach triplicate. evaluated Dashed in µ triplicate.lines, uninduced Dashed control;lines, uninduced open circles, control; low mupirocin open circles, induction low mupirocin (0.032 g induction/mL); gray (0.032 diamonds, µg/mL); moderate gray mupirocin induction (0.32 µg/mL); black squares, high mupirocin induction (3.2 µg/mL). Antibiotic diamonds, moderate mupirocin induction (0.32 µg/mL); black squares, high mupirocin induction (3.2 abbreviations are as follows: CPT, ceftaroline; DAL, dalbavancin; DAP, daptomycin; ORI, oritavancin; µg/mL). Antibiotic abbreviations are as follows: CPT, ceftaroline; DAL, dalbavancin; DAP, TLV, telavancin; VAN, vancomycin. Uninduced and low-induction exposures were not significantly daptomycin; ORI, oritavancin; TLV, telavancin; VAN, vancomycin. Uninduced and low-induction different at any time point with the exception of CPT and VAN where the two exposures each differed exposures were not significantly different at any time point with the exception of CPT and VAN at 48 h (p < 0.01). Moderate and high mupirocin induction were essentially indistinguishable from where the two exposures each differed at 48 h (p < 0.01). Moderate and high mupirocin induction each other and significantly different from uninduced strains (p < 0.01) at all time points and for all were essentially indistinguishable from each other and significantly different from uninduced strains exposures with the exception of ORI (p > 0.05). (p < 0.01) at all time points and for all exposures with the exception of ORI (p > 0.05). Antibiotics 2020, 9, 789 3 of 7 Table 1. Time to bactericidal activity under low induction conditions. Under low mupirocin exposure, MDK is prolonged in an isolate- and antibiotic-dependent manner. Dashed line (—), MDK not achieved over 48 h; *, p < 0.05. MDK (Uninduced, h) MDK (Low Induction, h) Strain Name CPT DAL DAP ORI TLV VAN CPT DAL DAP ORI TLV VAN 29213 — 19 0.6 1 0.0 1 0.0 37 0.4 13 0.6 — 24 0.1 * 47 1.5 * 2 0.5 48 0.0 * 21 1.0 * ± ± ± ± ± ± ± ± ± ± BSN10 39 0.8 — 2 0.0 1 0.1 38 5.9 22 0.4 — — 13 1.1 * 1 0.2 44 6.1 — ± ± ± ± ± ± ± ± BSN11 28 1.0 35 4.0 1 0.0 1 0.0 14 0.2 18 3.9 36 11.0 46 2.9 * 1 0.1 1 0.0 44 6.4 * 37 9.6 ± ± ± ± ± ± ± ± ± ± ±

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