\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[greek,english]{babel}



\usepackage{float}








\begin{document}

\title{Oxacillin plus ertapenem rapidly clears persistent left ventricular
assist device-related methicillin-susceptible Staphylococcus aureus
bacteremia}



\author[1]{H Andrew Wilsey}%
\author[1]{Barbara Pisani}%
\author[1]{Thomas O’Neill J}%
\affil[1]{Wake Forest Baptist Medical Center}%


\vspace{-1em}



  
  \date{May 25, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
There is an increasing use of left ventricular assist devices (LVADs) as
bridge to transplantation or permanent destination therapy in the heart
failure patient population. Infection remains a common complication in
LVADs, with Gram-positive skin flora as predominant pathogens
implicated, including \emph{Staphylococcus aureus}. While there is
emerging evidence for synergistic antibiotic combinations with
methicillin resistant \emph{Staphylococcus aureus,} there remains a
significant gap in the literature for persistent methicillin susceptible
\emph{Staphylococcus aureus (}MSSA) bacteremia. In this article, we
describe the first successful treatment of persistent LVAD-related
bacteremia with salvage oxacillin plus ertapenem. The salvage therapy
described here must be balanced by the risks for toxicity, impact on
resistance, microbiota disruption, drug shortages, and patient costs.
This combination warrants further evaluation in the clinical setting to
better establish its role in our expanding patient population.%
\end{abstract}%



\sloppy


\emph{Title}

Oxacillin plus ertapenem rapidly clears persistent left ventricular
assist device-related methicillin-susceptible \emph{Staphylococcus
aureus} bacteremia

\emph{Authors:}

H Andrew Wilsey, PharmD, BCCCP\textsuperscript{1}; Barbara Pisani,
DO\textsuperscript{2}; Thomas J O'Neill IV, MD, PhD\textsuperscript{2};

1: Department of Pharmacy, Atrium Health Wake Forest Baptist, Winston
Salem, NC

2: Division of Cardiology, Department of Internal Medicine, Atrium
Health Wake Forest Baptist, Winston Salem, NC

Corresponding Author: H Andrew Wilsey, PharmD, BCCCP, 1 Medical Center
Boulevard, Winston-Salem BC 27157 hwilsey@wakehealth.edu ; ORCID
0000-0003-3672-1929

Co-Author emails: bpisani@wakehealth.edu tjoneill@wakehealth.edu

\emph{Ethics and integrity statement:} The authors have no conflicts of
interest to declare. No funding was utilized for this manuscript.
Patient was informed of risks and benefits of allowing their information
to be used in this case report and provided signed consent.

\emph{Abstract:}

There is an increasing use of left ventricular assist devices (LVADs) as
bridge to transplantation or permanent destination therapy in the heart
failure patient population. Infection remains a common complication in
LVADs, with Gram-positive skin flora as predominant pathogens
implicated, including \emph{Staphylococcus aureus} . While there is
emerging evidence for synergistic antibiotic combinations with
methicillin resistant \emph{Staphylococcus aureus,} there remains a
significant gap in the literature for persistent methicillin
susceptible\emph{Staphylococcus aureus (} MSSA) bacteremia. In this
article, we describe the first successful treatment of persistent
LVAD-related bacteremia with salvage oxacillin plus ertapenem. The
salvage therapy described here must be balanced by the risks for
toxicity, impact on resistance, microbiota disruption, drug shortages,
and patient costs. This combination warrants further evaluation in the
clinical setting to better establish its role in our expanding patient
population.

\emph{Key words}

Bacteremia, LVAD infection, \emph{Staphylococcus aureus,} combination
therapy, oxacillin, ertapenem

\emph{Introduction}

The management of end stage heart failure remains limited by donor
availability and recipient candidacy, which has resulted in increasing
use of mechanical circulatory support (MCS) as bridge to transplantation
or permanent destination therapy. Left ventricular assist devices
(LVADs) offload a failing left ventricle, enhancing patient survival and
quality of life. As newer generations of LVADs continue to reduce
thrombosis risk our MCS patient population will continue to expand.
However, infection remains a significant complication, increasing a
patient's morbidity and mortality. A patient's driveline is the
percutaneous tube connecting the internal VAD pump and the
extracorporeal controlled unit. The driveline renders a patient highly
susceptible to microbial contamination and represents a common source of
infection. For this reason, Gram-positive skin flora are commonly
implicated in LVAD-associated infections, including \emph{Staphylococcus
aureus} \textsuperscript{1}\emph{.} The management of this patient
population is guided by observational data and expert opinion and may be
further complicated by pathogen type, infection location, and patient
surgical/transplant candidacy status. While there is emerging data on
synergistic antibiotic combinations for the management of methicillin
resistant \emph{Staphylococcus aureus,} there remains a significant gap
in the literature for persistent methicillin
sensitive\emph{Staphylococcus aureus (} MSSA) \textsuperscript{2}. There
are a handful of both \emph{in-vitro} and \emph{in-vivo} studies that
suggest a synergistic effect of cefazolin and ertapenem combination
therapy for persistent MSSA \textsuperscript{3--5}. Here we describe the
successful use of oxacillin and ertapenem combination therapy in the
treatment of LVAD-associated persistent MSSA bacteremia.

\emph{Case presentation}

A 51-year-old male with history of ischemic cardiomyopathy had an LVAD
HeartMate III implanted in November 2019. He developed his first
VAD-specific infection in April 2020, further classified as
late-onset\textsuperscript{6}. The patient's driveline drainage culture
was positive for MSSA and was started on oral doxycycline 100mg every 12
hours which was continued as suppressive therapy. September 2021,
patient was admitted with worsening driveline infection (DLI). During
this admission, he underwent incision and drainage with excisional
debridement of infected subcutaneous tissue. MSSA with the same
susceptibility patterns as prior wound culture was isolated and after
several days of intravenous cefazolin, patient was transitioned to oral
doxycycline 100mg and oral rifampin 300mg every 12 hours. Rifampin
treatment was anticipated for 6 weeks, however patient was unable to
tolerate due to gastrointestinal adverse effects and stopped therapy at
4 weeks. The patient was readmitted four months following surgical
debridement, found to have MSSA on blood cultures. Susceptibilities
remained similar, with an increase from \textless{}0.25 to 0.5 MIC
reported for oxacillin. He was started on cefazolin for one day, and
then transitioned to oxacillin 2g every 4 hours. Complicating care,
patient was noted to have a small mass concerning for vegetation on his
tricuspid valve and was pacemaker dependent. The patient remained
clinically stable but with ongoing bacteremia despite 7 days of targeted
therapy. Source control was hindered given patient was not a candidate
for transplant, given his current smoking status and pacemaker
dependency. Ultimately, the decision was made to add ertapenem 1g every
24 hours to 12g continuous infusion oxacillin for salvage therapy.
Within 24 hours of starting combination therapy, patient had resolution
of persistent bacteremia. He was kept on ertapenem 1g every 24 hours for
7 days total and transitioned to intravenous oxacillin 12g a day for 6
weeks. No adverse events were noted with the addition of ertapenem and
remains without relapse for 3 months.

\emph{Discussion}

The successful management of persistent MSSA bacteremia is highly
dependent on source control, which is a significant challenge in the
LVAD patient population. Source control may only be achieved via a
device exchange, device removal during orthotopic heart transplant or
explantation. It is important to stress here that unlike other medical
device-related infections, exchange of VADs for source control is
generally avoided due to the complexity of the surgical procedure and
concerns regarding risk of reinfection of newly implanted device.
Patients who are a candidate for neither transplant, removal nor
replacement must rely on medical management. Aminoglycosides are
generally discouraged given lack of clear-cut efficacy and documented
toxicity issues. Rifampin may be considered, but frequently not started
until cultures clear to avoid development of resistance. In recent
years, much attention has been given to the synergistic combination of
beta-lactam antibiotics for the management for MRSA
bacteremia\textsuperscript{2}. However, few data exist for therapeutic
options for persistent MSSA bacteremia.

Ulloa et al recently published the largest case series of 11 patients
with persistent MSSA bacteremia who were successfully treated with
salvage ertapenem and cefazolin \textsuperscript{4}. The mean duration
of bacteremia was 6 days (range, 4-9 days) on appropriate antibiotics.
Interestingly, among the 9 cases where blood cultures were collected
daily, bacteremia cleared within 24 hours of ertapenem in 8 cases
(88\%). Even more so remarkable considering two of these cases were
tricuspid valve endocarditis with \emph{\textgreater{}} 2 cm
vegetations. This robust response even without obtaining surgical source
control appears to be mirrored in our patient case. Within in the LVAD
population, there exists one published case series. Carenas-Alvarez et
al. reported 2 cases of refractory MSSA bacteremia in LVAD recipients
successfully treated with cefazolin plus ertapenem \textsuperscript{3}.
The first patient had ertapenem added to his therapy after 10 days of
cefazolin and cleared cultures one day after starting salvage treatment.
The second patient developed MSSA bacteremia through suppressive
intravenous cefazolin and was therefore treated with intravenous
oxacillin. However, after eight days of persistently positive cultures,
switched to cefazolin with ertapenem with resolution of bacteremia
within 24 hours.

While several studies have noted increased tolerability and even
improved outcomes in patients receiving cefazolin as compared to anti
staphylococcal penicillins (ASP), providers may have concerns regarding
potential inferior cefazolin activity under high inoculum
conditions\textsuperscript{4}. The combination of ASP and ertapenem has
even less data -- the largest published in late 2021. El-Dalati describe
eight patients treated with ASP (oxacillin or nafcillin) and ertapenem.
Combination treatment was initiated following 5 days of persistent
bacteremia. Blood sterility was achieved in all patients; six patients
had documented clearance within one day \textsuperscript{8}. Here,
oxacillin plus ertapenem was the most common regimen, suggesting that
salvage combination therapy may be used with either ASP or cefazolin.
This conclusion is strengthened in our patient case. To the best of our
knowledge, this is the first report describing use of an ASP based
salvage regimen in LVAD-associated bacteremia.

In nearly all cases, a rapid clearance of blood cultures was observed.
The basis for this combination leverages differences in affinity for
various protein binding proteins (PBPs). Beta-lactam antibiotics exert
their bactericidal effects by irreversibly interfering with the enzymes
involved in cell wall synthesis, PBPs. Inhibiting enzymatic activity
results in impaired cell wall synthesis, cell wall destabilization, and
subsequently cell death. Carbapenem antibiotics have a higher affinity
for PBP1 as compared to antistaphylococcal beta-lactams. Therefore,
their addition would complement the relative proclivity of cefazolin and
ASP for PBP2. While oxacillin is thought to have higher affinity for
PBP1, the data presented in this case report and by El-Dalati et al.
suggest oxacillin as a suitable agent for this salvage
therapy\textsuperscript{8}. Oxacillin may exhibit a similar mechanism
for synergy with complimentary PBP-2 binding or may possibly offer more
complete PBP1 saturation.

This combination has repeatedly demonstrated a clear and rapid
resolution of persistent bacteremia. This has serious consequences for
the MCS patient population, as time to blood sterilization with S.
aureus may be associated with improved clinical outcomes and lower rates
of death \textsuperscript{9} . However, there are certainly risks
associated with this salvage therapy that warrant consideration.
Virtually every antibiotic has been associated with \emph{Clostridioides
difficile} infection (CDI). Therefore, it is important to consider the
risk-benefit of adding a secondary antimicrobial agent that may result
in long-lasting changes to the human gut microbiota. Similarly, the
introduction of antibiotics to our patient population invariably leads
to resistance. Further investigation is warranted to assess the full
impact of carbapenem use on patient and community resistance patterns.
Questions remain regarding the choice between ASP as compared to
cefazolin in the setting of risk of acute kidney injury versus efficacy
with inoculum conditions. Lastly and perhaps most importantly, further
research is needed to capture whether rapid blood sterilization offers a
patient-centered outcome benefit.

\emph{Future directions and conclusion}

In conclusion, we present a case of the successful use of oxacillin and
ertapenem for the management of persistent MSSA bacteremia in an LVAD
patient. \emph{Staphylococcus aureus} is notorious for the common
metastatic spread of infection, which has been correlated with the
duration of bacteremia. Prompt clearance of blood cultures was noted
within 24 hours from combination initiation, similarly to available
published data. Based on in vitro data, cefazolin had been utilized
previously for salvage therapy. This is the first case report in the MCS
setting describing successful use of oxacillin with ertapenem. The
salvage therapy described here must be balanced by the risks for
toxicity, impact on resistance, microbiota disruption, drug shortages,
and patient costs. Questions regarding optimal timing of initiation of
ertapenem, duration of combination therapy, repeated efficacy of
combination therapy, and extrapolation to other MCS patients in which
source control may be challenging. It is also critical to recognize that
no patient-centered benefit has been established and combination therapy
risks have not been fully explored. Ultimately, this combination
warrants further evaluation in the clinical setting to better establish
its role in patient care.

\emph{References}

1. Kusne S, Mooney M, Danziger-Isakov L, et al. An ISHLT consensus
document for prevention and management strategies for mechanical
circulatory support infection. \emph{J Heart Lung Transplant} .
2017;36(10):1137-1153. doi:10.1016/j.healun.2017.06.007

2. Wilsey HA, Burgess DR, Burgess DS. Focusing the Lens on the CAMERA
Concepts: Early Combination \selectlanguage{greek}β-\selectlanguage{english}Lactam and Vancomycin Therapy in
Methicillin-Resistant Staphylococcus aureus Bacteremia. \emph{Antimicrob
Agents Chemother} . 2020;64(7):e00360-20. doi:10.1128/AAC.00360-20

3. Cardenas-Alvarez JL, Suarez J, Motoa G, et al. Cefazolin plus
ertapenem and heart transplantation as salvage therapy for refractory
LVAD infection due to methicillin-susceptible Staphylococcus aureus: A
case series. \emph{J Card Surg} . 2021;36(12):4786-4788.
doi:10.1111/jocs.16040

4. Ulloa ER, Singh KV, Geriak M, et al. Cefazolin and Ertapenem Salvage
Therapy Rapidly Clears Persistent Methicillin-Susceptible Staphylococcus
aureus Bacteremia. \emph{Clin Infect Dis Off Publ Infect Dis Soc Am} .
2019;71(6):1413-1418. doi:10.1093/cid/ciz995

5. Sakoulas G, Olson J, Yim J, Singh NB, Kumaraswamy M, Quach DT, Rybak
MJ, Pogliano J, Nizet V. Cefazolin and Ertapenem, a Synergistic
Combination Used To Clear Persistent Staphylococcus aureus Bacteremia.
Antimicrob Agents Chemother. 2016 Oct 21;60(11):6609-6618. doi:
10.1128/AAC.01192-16.

6. Hannan MM, Husain S, Mattner F, et al. Working formulation for the
standardization of definitions of infections in patients using
ventricular assist devices. \emph{J Heart Lung Transplant} .
2011;30(4):375-384. doi:10.1016/j.healun.2011.01.717

7. Qu Y, Peleg AY, McGiffin D. Ventricular Assist Device-Specific
Infections. \emph{J Clin Med} . 2021;10(3):453. doi:10.3390/jcm10030453

8. El-Dalati S, Sridaran S, Uricchio M, Kline EG, Shields R. Oxacillin
plus ertapenem combination therapy leads to rapid blood culture
clearance and positive outcomes among patients with persistent MSSA
bacteraemia: a case series. \emph{JAC-Antimicrob Resist} .
2021;3(3):dlab148. doi:10.1093/jacamr/dlab148

9. Defining persistent Staphylococcus aureus bacteraemia: secondary
analysis of a prospective cohort study - ScienceDirect. Accessed January
5, 2022.
https://www.sciencedirect.com/science/article/pii/S1473309920304473?via\%3Dihub

\selectlanguage{english}
\FloatBarrier
\end{document}

