Jonathan Hand, MD1404165/UQ404165_OA.pdf · Jonathan Hand, MD1 Gopi Patel, MD MS2* *Corresponding Author 1 Jonathan Hand, MD Department of Infectious Diseases Ochsner Clinic Foundation

Multidrug-resistant organisms in liver transplant — mitigating risk and managing infections

Authors:

Jonathan Hand, MD1

Gopi Patel, MD MS2*

*Corresponding Author

1

Jonathan Hand, MD

Department of Infectious Diseases

Ochsner Clinic Foundation

Senior Lecturer, The University of Queensland School of Medicine, Ochsner Clinical School

1514 Jefferson Highway

New Orleans, LA 70121

Phone (504) 842-4005

Fax (504) 842-5254

[email protected]

2

Gopi Patel, MD MS

Assistant Professor, Division of Infectious Diseases

Department of Medicine, Icahn School of Medicine at Mount Sinai

One Gustave L. Levy Place, Box 1090

New York, NY 10023

Phone (212) 241-6741

Fax (212) 987-4006

[email protected]

Key words: carbapenem-resistant Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter

baumannii, methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus,

liver transplant

No grants or conflicts of interest

This article has been accepted for publication and undergone full peer review but has not beenthrough the copyediting, typesetting, pagination and proofreading process which may lead todifferences between this version and the Version of Record. Please cite this article as an‘Accepted Article’, doi: 10.1002/lt.24486

This article is protected by copyright. All rights reserved.

Abstract:

Liver transplant recipients are vulnerable to infections with multidrug-resistant

pathogens. Risk factors for colonization and infection with resistant bacteria are ubiquitous

and unavoidable in transplantation. During the past decade, progress in transplantation and

infection prevention has contributed to the decreased incidence of infections with methicillin-

resistant Staphylococcus aureus. However, even in the face of potentially effective antibiotics,

vancomycin-resistant enterococci continue to plague liver transplantation. Gram-negative

bacilli prove to be more problematic and are responsible for high rates of both morbidity and

mortality. Despite the licensure of novel antibiotics, there is no universal agent available to

safely and effectively treat infections with multidrug-resistant Gram-negative organisms.

Currently, efforts dedicated toward prevention and treatment require involvement of multiple

disciplines including transplant providers, specialists in infectious diseases and infection

prevention, and researchers dedicated to the development of rapid diagnostics and safe and

effective antibiotics with novel mechanisms of action.

Introduction

Even with great improvements in infection prevention, surgical technique, and

immunosuppression; bacterial infections remain responsible for poor outcomes in liver

transplantation. In an era of prolonged wait times, repeated and unavoidable exposures to

both healthcare and antibiotics place liver transplant (LT) candidates and recipients at high risk

for both colonization and infection with multidrug-resistant organisms (MDROs). Multidrug

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John Wiley & Sons, Inc.

Liver Transplantation


resistance is frequently defined as bacteria resistant to at least one agent in at least three

different antibiotic classes(1). Despite this accepted definition, the definitions applied in

studies describing MDROs are variable. MDRO colonization has been associated with

subsequent infection and surgical complexities, requirement for immunosuppressive therapy,

and necessary invasive interventions (e.g., central venous catheters, urinary catheters, and

mechanical ventilation) also add to the risk of MDRO infection in this susceptible population. In

the absence of post-transplant complications, bacterial infections are more common early post-

LT(2). Rarely donor transmission of a MDRO has been reported.

Delays in effective empirical therapy, lack of experience with older and newer agents,

and ever-changing susceptibility profiles in the setting of inadequate source control or selective

antibiotic pressures contribute to the difficulties in treating patients infected with MDROs,

specifically MDR Gram-negative bacilli. In this review, we highlight risk factors and available

treatment for some of the more common and problematic MDROs encountered in liver

transplantation.

Multidrug-resistant Gram-positive cocci

Historically, infections with Gram-positive organisms, specifically Staphylococcus aureus

and enterococci, were a common source of complications post-LT. Public awareness of the

impact of methicillin-resistant Staphylococcus aureus (MRSA) likely has contributed to advances

in both prevention and treatment of staphylococcal infections(3). Unfortunately, infections

with enterococci continue to be common among LT recipients. Vancomycin-resistant

enterococci (VRE), although less virulent, can confound an already problematic post-LT course

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especially in the setting of surgical complications and prolonged hospital stays. The advent of

both linezolid and daptomycin has changed the overall landscape of enterococcal infections,

however, resistance has been described and novel therapeutics remain unproven(4-8).

Methicillin-resistant Staphylococcus aureus (MRSA)

Overall rates of invasive MRSA are declining(9). The precipitous drop in MRSA infections

coincide with increased emphasis on infection prevention practices including rigorous

adherence to hand hygiene and isolation precautions, perioperative skin antisepsis, central

venous catheter insertion and maintenance bundles, active surveillance with or without

decolonization, and universal daily bathing with chlorhexidine gluconate in select settings like

intensive care units (ICUs)(10).

Most studies exploring the risk factors, prevalence, and incidence of MRSA in liver

transplantation are single center evaluations from the United States in the setting of active

surveillance(11). MRSA infection reportedly occurs in 4-23% of LT recipients(12) though more

contemporary studies suggest lower rates(13). Colonization with MRSA, specifically nasal

carriage, is a significant risk factor for subsequent MRSA infection post-LT(14, 15). A recent

meta-analysis estimated the prevalence of MRSA colonization pre-LT to be nearly 12% with

similar rates (13%) post-LT. In this study pre- and post-LT MRSA carriage was associated with

close to a 6-fold and 11-fold respective increase in MRSA infection(11).

Other cited risk factors for MRSA infection have been summarized elsewhere(16) but

include prolonged hospitalization, broad-spectrum antibiotic use, primary cytomegalovirus

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infection, extended ICU stay, and peritonitis. Donor-derived MRSA infections have been

described(17-19).

Isolated MRSA colonization has not been directly associated with mortality(11, 15). The

association between MRSA infection and mortality in liver transplantation is evolving. More

recent studies do not demonstrate an increased risk of mortality(12, 14, 15).

While rare in LT recipients, vancomycin-intermediate S. aureus (VISA) and

heteroresistant VISA (hVISA) can potentially complicate treatment of MRSA. Description of a

French cohort implies increased prevalence (13/48, 27%) of hVISA was the result of clonal

transmission(16). Vancomycin-resistant S. aureus (VRSA) has not yet been reported in liver

transplantation. Nevertheless, vancomycin resistance is a viable concern given the potential for

transfer of enterococcal vanA elements to S. aureus(20) and the prevalence of VRE in the LT

population.

Vancomycin arguably remains the mainstay for treatment of MRSA(21) and the

treatment of MRSA infections in transplantation has been reviewed in detail(16). Commonly

used licensed alternatives to vancomycin include linezolid and daptomycin. Data exist

suggesting increased rates of clinical failure with vancomycin in the setting of higher

vancomycin minimum inhibitory concentrations (> 1.0 mg/L)(22). Evidence suggests the non-

inferiority of daptomycin in the treatment of MRSA bacteremias(23). Retrospective studies

suggest daptomycin may portend better outcomes in the setting of bacteremias when MIC > 1

mg/L (24, 25). However, prospective trials assessing the superiority of daptomycin over

vancomycin in the setting of elevated MICs are in their infancy. A recent multicenter evaluation

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suggested no difference in composite failures between vancomycin and daptomycin, but higher

rates of nephrotoxicity in patients receiving vancomycin(26).

Of increasing concern is resistance to both daptomycin and linezolid is being reported.

What is increasingly alarming is that resistance is being described in the absence of drug

exposure(27).

Recently, several agents with potential activity against MRSA have been licensed

primarily for the treatment of skin and soft tissue infections. They include the

lipoglycopeptides, oritavancin, telavancin, and dalbavancin; ceftaroline, an antistaphylococcal

cephalosporin; and tedezolid, a new oxazolidinone. Although in vitro data exist suggesting

activity against MRSA, clinical data in transplant recipients are scarce.

Though a single center’s experience demonstrated a decrease in both S. aureus infection

and colonization in LT patients with targeted active surveillance, decolonization, and infection

prevention measures(28) recommendations and randomized trials regarding timing, frequency

and specific decolonization regimens are limited(11). In the setting of deceased donor

transplantation, timing and durability of decolonization remain unclear.

Vancomycin-resistant enterococci (VRE)

Unlike MRSA, acquisition of VRE remains associated primarily with exposure to

healthcare. Antibiotic use, length of hospitalization, and environmental contamination are

associated with VRE acquisition. Similar to MRSA, colonization frequently precedes

infection(11). A recent meta-analysis, inclusive of studies from the US and Brazil, estimated

the prevalence of pre- and post-LT VRE colonization to be 12% and 16% respectively. If this

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study was exclusive to the US, the prevalence of colonization was 16% pre- and 22% post-LT.

Pre-LT VRE colonization was associated with a nearly 7-fold increase in VRE infection, with an

additional 8-fold increase post-transplantation(11).

Biliary complications (e.g., leaks and strictures) with subsequent re-explorations and

interventions predispose LT recipients to VRE(20, 29, 30). Prior to the advent of quinopristin-

dalfopristin and linezolid, VRE-associated morality rates ranged between 33 to 82% in LT

patients(31). Acquisition post-transplantation was associated with the highest mortality

risk(15, 29).

Treatment of VRE in organ transplantation has been extensively reviewed(4) and the

two most commonly used antibiotics, daptomycin and linezolid, are safe and well-tolerated in

this population(32, 33). Linezolid-resistant VRE has been described in LT recipients in the

setting of linezolid exposure as well as horizontal transmission(34, 35). Daptomycin-

nonsusceptible enterococci have been recovered in liver transplant recipients with and without

prior exposure to daptomycin(5, 36).

Other agents with potential activity against VRE include telavancin and ceftaroline.

Neither demonstrates reliable activity against E. faecium although televancin may have activity

against vanB strains. Oritavancin demonstrates in vitro activity against vanA and vanB

harboring strains of enterococci, however, clinical data for its use in severe infections are

lacking. Tedezolid has demonstrated in vitro activity against linezolid, daptomycin, and

vancomycin-resistant staphylococci and enterococci(6). Increasing in vitro and case-specific

data are emerging regarding combination therapy for the treatment of VRE(7, 8). No specific

combination has been studied in clinical trials.

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Outside of outbreaks or hyperendemicity, there is no established role for active VRE

surveillance in LT candidates or recipients(20). However, known colonization may allow for

alteration of perioperative regimens to include anti-VRE therapy(37). Contact precautions

should be implemented when asymptomatic colonization is established(20) to prevent

horizontal transmission especially in high-risk settings like transplantation units or ICUs.

Resistant Gram-negative bacilli

During the last 15 years, a shift in the microbiology of post-LT infections has occurred

with a marked increase in Gram-negative infections(38). Accounts of multidrug-resistant Gram-

negative pathogens in LT recipients are growing with centers worldwide reporting rates of

>50%(39, 40). Risk Factors for MDR Gram-negative infections post-LT include re-exploration,

abdominal infections, and acute allograft rejection(39). Infection with resistant isolates is

associated with significantly increased mortality rates(39-42).

Extended Spectrum Beta-Lactamase (ESBL) producing Enterobacteriaceae

The production of β-lactamases, enzymes able to hydrolyze β-lactam antibiotics, is a

common cause of resistance among Enterobacteriaceae, including Escherichia coli and

Klebsiella pneumoniae. Extended-spectrum β-lactamase (ESBL) producing Enterobacteriacae

are genetically diverse and have been recovered in both the community and healthcare

settings. It is not surprising that in a population with universal exposure to antibiotics and

healthcare, these pathogens are frequently recovered in LT candidates and recipients.

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Rates of ESBL infection vary from 5.5-12.8% in non-endemic areas(43). In endemic

areas, rates can be considerably higher and mortality in the setting of infection has been

reported to be as high as 40% despite appropriate antibiotics(44). Independent predictors of

gastrointestinal carriage of ESBLs in LT candidates include recent history of spontaneous

bacterial peritonitis and recent receipt of a β-lactam antibiotic(44). In addition to pre-LT

colonization, advanced liver disease and repeated explorations are cited risk factors for

subsequent infection with ESBL-producing organisms.

Concomitant carriage of multiple resistance determinants confounds the treatment of

infections with ESBL-producing Enterobacteriaceae. Carbapenems remain the drugs of choice.

Despite in vitro susceptibilities, piperacillin-tazobactam and cefepime are not reliable in severe

infections but may be used with less severe infections where the agent concentrates well like

urinary tract infections.

Similar to MRSA and VRE, the Centers for Disease Control and Prevention (CDC)

recommends contact isolation be routinely used for all ESBL-producing Enterobacteriaceae

irrespective of species(45). Controversy exists regarding the need for these precautions for

patients colonized or infected with ESBL-producing E. coli as horizontal transmission appears to

be low as compared to to ESBL-producing K. pneumoniae(46, 47) The practicality of excluding

ESBL-producing E. coli from isolation protocols may be challenging especially in high risk

settings like liver transplantation.

Carbapenem-resistant Enterobacteriaceae (CRE)

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Carbapenem-resistant Enterobacteriaceae (CRE), particularly carbapenem-resistant K.

pneumoniae (CRKP), have been increasingly described among organ transplant recipients in the

past decade(48). Carbapenem resistance can be conferred by a variety of resistance

mechanisms; however, expression of carbapenemases is most common. In the US, expression

of K. pneumoniae carbapenemases (KPCs) is the most frequently observed mechanism of

resistance. However, recovery of metallo-β-lactamases (MBL)(49) and carbapenem-hydrolyzing

class D carbapenemases (oxacillinase-48 (OXA-48)) has been described(50). CRE often is

multidrug-resistant and no available agent (Table 1) demonstrates universal activity, thus

further complicating treatment.

Reported rates of CRKP in LT recipients range from 6 – 12.9%(51, 52) accounting for 23%

of all bacterial infections post-LT in one center in New York(53). In LT recipients, reported

associated mortality ranges from 18% to nearly 80%(51, 53-55). Non-transplant specific risk

determinants for acquisition and infection with CRKP include exposure to broad-spectrum

antibiotics, high prevalence of CRKP, and severity of illness (e.g., need for invasive devices or

ICU stay)(56). These risk factors are intrinsic to transplantation, especially liver transplantation.

Most published studies evaluating the risk and impact of CRKP in LT are single center and in the

setting of incomplete assessment of colonization status.

Contemporary studies of large cohorts of LT patients with CRKP cite advanced liver

disease, hepatocellular carcinoma, Roux-en-Y anastomosis, post-operative biliary leaks, renal

replacement therapy, prolonged ventilator support, and recurrence of hepatitis C virus

infection as significant predictors of subsequent CRKP infection(51, 54). When the information

is available, pre-LT colonization appears to be a risk factor for post-LT CRKP infection(54, 55). In

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an Italian cohort, 4.6% of pre-LT patients were colonized with CRKP(54). Those LT recipients

colonized prior to LT were at higher risk of LT infection than those not colonized. Those LT

recipients with colonization detected after transplantation appeared to have the highest attack

rates(54).

The treatment of CRE is exceedingly complex and has recently been reviewed(57).

Although none provide universal activity against CRE, available agents with potential activity

against these pathogens include aminoglycosides, polymyxins (colistin and polymyxin B), and

tigecycline. In the setting of cystitis, fluoroquinolones, fosfomycin and nitrofurantoin can

potentially be used.

Much debate surrounds the use of polymyxins: drug (colistin versus polymyxin B), dose,

and the emergence of resistance on therapy(57). In addition to source control(58), many

experts recommend the use of combination therapy, with or without carbapenems, to treat

CRE(48, 59, 60). The success of specific combinations may rely on the underlying resistance

mechanisms highlighting the role of rapid diagnostics(60). Trials systematically evaluating the

role of polymyxin-based combination therapy are in progress.

The recent licensure of ceftazidime-avibactam adds to the arsenal of antibiotics

available to treat CRE. In vitro activity depends on the specific carbapenemase being expressed

with no reliable activity against MBLs (e.g., New Delhi MBL (NDM)). Resistance among KPC-

producing K. pneumoniae has been recently reported(61). Plazomicin (ACHN-490), an

investigational aminoglycoside, demonstrates potent in vitro activity against CRE including

those producing MBLs. Intravenous fosfomycin has been used to treat systemic infections

outside of the US(42, 57).

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Potential eradication of CRKP gastrointestinal colonization using oral gentamicin and

oral polymixin E (colistin) has been evaluated with some success(62). However, subsequent

analyses of breakthrough post-treatment isolates reveal significant increases in rates of colistin

and gentamicin resistance(63). Donor transmission of CRE has been reported(64, 65).

Colonization or infection with CRE is not an absolute contraindication to liver

transplantation. High associated mortality rates should prompt providers to take pause and

weigh this risk as they would other comorbid conditions prior to proceeding with

transplantation.

Multidrug-resistant Pseudomonas aeruginosa

Pseudomonas aeruginosa has the unique ability to harbor and accrue numerous

resistance determinants(66) making multidrug resistance frequent. Recovery of MDR P.

aeruginosa is not uncommon in organ transplantation(48). P. aeruginosa recovered from organ

transplant recipients demonstrates higher rates of carbapenem resistance compared to isolates

from non-transplant recipients(67). Reports in LT recipients are often in the setting of single

center outbreaks or high local prevalence(68, 69). Rates of P. aeruginosa bloodstream

infections in LT range from 6.5-10%(48), with over 50% of isolates demonstrating multiple drug

resistance(39).

Although recommended by many experts, the role of routine combination therapy for

the treatment of P. aeruginosa infections remains controversial(70). Many may want to

consider combination therapy up front while awaiting susceptibilities especially in the setting of

unpredictable resistance patterns. Both ceftazidime-avibactam and ceftolozane-tazobactam do

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demonstrate activity versus select strains(57). Neither novel cephalosporin/β-lacatamase

inhibitor combination inhibits MBLs. Plazomicin potentially has in vitro activity against some

isolates of P. aeruginosa. However, like with CRE, the mechanism of underlying aminoglycoside

resistance influences activity.

Carbapenem-resistant Acinetobacter baumannii (CRAB)

Similar to multidrug resistance among P. aeruginosa, the definition of multidrug

resistance(1) varies across publications describing local experiences with Acinetobacter

baumannii in organ transplantation. Most reports evaluating risks and outcomes associated

with acquisition carbapenem-resistant Acinetobacter baumannii (CRAB) reflect the experience

of single centers and are not exclusive to LT(71). CRAB has been reported in LT recipients with

resistance rates of up to 95%(72, 73)Healthcare-associated pneumonia, including ventilator-

associated pneumonia, is the most commonly reported presentation of CRAB infection in LT

recipients. In some centers, up to 24% of bloodstream infections in LT recipients were caused

by A. baumanii with multidrug resistance found in >50% of isolates(39, 74, 75) Like the other

MDROs described, organ transplant recipients colonized with CRAB may subsequently develop

infection(76). In-hospital mortality related to Acinetobacter infections can be unacceptably

high in LT(74) with associated mortality rates of over 50%(76, 77)and up to 90% in the ICU(78).

Treatment of MDR A. baumannii remains difficult. Studies from a single medical center

in the US suggest that combination therapy with colistin and a carbapenem portend better

survival rates among organ transplant recipients(76). However, the emergence of colistin

resistance is not uncommon(73, 76).

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In addition to polymxins, aminoglycosides, minocycline, and tigecycline have been used

to treat CRAB infections with varying degrees of success. Sulbactam, a β-lactamase inhibitor,

demonstrates intrinsic activity against A. baumannii. In many centers, ampicillin-sulbactam

demonstrates the best activity against CRAB(42) and based on local susceptibility patterns may

be the most appropriate empirical choice for the treatment of suspected A. baumannii

infection. In terms of newer agents, neither ceftazidime-avibactam nor ceftolozane-

tazobactam demonstrates reliable activity against A. baumannii. Depending on the mechanism

of aminoglycoside resistance, plazomicin may have activity against specific isolates particularly

in combination with carbapenems(79).

Conclusion

Most bacterial infections occur early after transplantation in the setting of

hospitalization and intensive care. Infection prevention and antibiotic stewardship(80) remain

paramount in mitigating the emergence and transmission of MDROs. In addition to strict

adherence to hand hygiene, isolation precautions, and environmental disinfection

recommendations; patient-specific bundles have been shown to decrease device-associated

infections and surgical site infections(81). Avoiding these healthcare-associated infections

may be the “easy pickings” in liver transplantation.

In terms of device-associated infections, daily assessment of continuing need for devices

(e.g., central venous catheters and urinary catheters) and prompt removal when no longer

necessary may offer substantial benefits to the post-transplant patient by decreasing the

infection risk and allowing early patient mobilization(81). Universal bathing with chlorhexidine

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gluconate to reduce MDRO acquisition remains debatable(82, 83) and has been untested in

liver transplantation specifically. Although active surveillance has been used in liver transplant

to identify patients requiring isolation and at-risk patients(37), the use of active surveillance

outside of an outbreak setting cannot be categorically recommended.

Diagnosing and treating infections in liver transplantation can be challenging(2). Early

and appropriate antibiotics in the setting of severe bacterial infections are associated with

better patient outcomes(84) (Figure 1). Consequently, broad-spectrum antibiotics are

frequently used as first-line in the setting of suspected infection irrespective of severity. This

empiric approach to antibiotics may lead to overuse and prolonged use as optimal treatment

regimens and durations for infectious syndromes in organ transplant recipients are not

specifically defined(85). Antimicrobial stewardship programs (ASP) have been shown to

decrease both antimicrobial overuse and prevalence of MDROs as well as improve clinical

outcomes (86). Unfortunately, studies evaluating ASP in organ transplantation are limited (85,

87, 88) and the extrapolation of therapeutic plans from existing non-transplant specific

guidelines can be divisive. A recent audit of a large Canadian transplant network found

significant opportunities for ASP in organ transplantation(88). With the disproportionate

presence of MDROs in liver transplant, these patients stand to significantly benefit from

prudent antibiotic use. Implementation of rapid diagnostics (e.g., Matrix-assisted laser

desorption/ionization (MALDI) or multiplex polymerase chain reaction (PCR) platforms) may

allow for early identification of pathogens allowing for earlier broadening, discontinuation, and

de-escalation of empiric regimens. Novel antibiotics targeting MDROs, specifically Gram-

negative bacilli, are limited (Table 1) and studies evaluating optimal therapeutic management

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are lacking. Thus, in order to preserve available antibiotics and decrease the risk for increased

resistance and for Clostridium difficile infections, the length of prescribed therapy should based

on culture data and patient response rather than arbitrary based on physician comfort. Studies

inclusive of liver transplant patients have demonstrated that each day of antibiotic exposure

increases likelihood of MDRO acquisition(56).

Finally, in the setting of a dearth of antibiotics, knowledge of local epidemiology should

influence empirical antimicrobial decision-making. Irrespective of the acuity of disease, LT

patients are likely to become colonized and/or infected with the MDRO that is most frequently

isolated in the units to which they are most commonly admitted. A pathogen common at one

center may not be common at another center and susceptibility profiles vary drastically.

Empiric broad-spectrum therapy, including multiple agents directed toward multidrug-resistant

Gram-negative bacilli in a severely ill patients may be appropriate, however prolonged therapy

in the absence of culture data is not. A multidisciplinary approach, including hepatologists,

surgeons, intensivists, infectious diseases physicians, pharmacists, and microbiologists, is

mandatory in order to improve the care of this growing population of patients and prevent

continuing recovery of relatively untreatable pathogens.

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Abbreviations:

ASP Antibiotic stewardship program

CDC Centers for Disease Control and Prevention

CRAB carbapenem-resistant Acinetobacter baumannii

CRE carbapenem-resistant Enterobacteriaceae

CRKP carbapenem-resistant Klebsiella pneumonia

ESBL extended-spectrum β-lactamase

hVISA heteroresistant vancomycin-intermediate Staphylococcus aureus

ICU intensive care unit

LT liver transplant

KPC Klebisella pneumoniae carbapenemases

MBL metallo-β-lactamase

MIC minimum inhibitory concentration

MDR multidrug-resistant

MDRO multidrug-resistant organism

MRSA methicillin-resistant Staphylcoccus aureus

NDM New Delhi metallo-β-lactamase

OXA oxacillinase

US United States

VISA vancomycin-intermediate Staphylcoccus aureus

VRE vancomycin-resistant enterococcus

VRSA vancomycin-resistant Staphylococcus aureus

Page 25 of 35




Table 1: Antibiotics commercially available or in advanced clinical trials with activity against carbapenem-resistant Gram-negative

bacilli*(57, 89, 90)

Carbapenem-resistant

Enterobacteriaceae

Carbapenem-

resistant

Pseudomonas

aeruginosa†

Carbapenem-

resistant

Acinetobacter

baumannii

Special considerations

and comments

KPC MBL (e.g.,

NDM)

OXA-48

Commercially available antibiotics

Aminoglycosides

(e.g., gentamicin,

tobramycin, amikacin)

X X X X X • Associated with

nephrotoxicity and

ototoxicity.

• Therapeutic drug

monitoring

recommended to

achieve optimal

bacterial killing

and decrease

toxicity.

Ceftazidime-avibactam X X X

Ceftolazone-tazobactam X

Fosfomycin X X X • Parenteral

formulation not

available in the US.

• Often used in

combination with

other agents

except for simple

cystitis.

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5051525354555657585960


Polymyxins (e.g., colistin

and polymyxin B)

X

X

X

X

X

• Studies suggesting

combination

therapy may

portend better

outcomes than

monotherapy.

• Associated with

nephrotoxicity and

neurotoxicity.

Tigecycline X X X Minimal • Associated with

increased

mortality. Not

recommended for

primary

bloodstream

infections due to

rapid

concentration into

tissues.

• Poor penetration

into urine.

Agents in advanced stages of development

Ceftaroline/avibactam X X Phase II, anti-MRSA

cephalosporin/ β -

lactamase inhibitor

Eravacycline X X X Phase III, fluorocycline

Imipenem/relebactam X X† Phase III, carbapenem/

β -lactamase inhibitor

Meropenem/vaborbactam X Phase III,

carbapenem/boronic

acid β - lactamase

Page 27 of 35



5051525354555657585960


inhibitor

Plazomicin X X X† Phase III,

aminoglycoside

KPC- Klebsiella pneumoniae carbapenemase, MBL- metallo-β-lactamase, OXA- oxacillinase, MRSA- methicillin-resistant

Staphylococcus aureus

* Susceptibilities vary depending on concomitant resistance mechanisms

† Dependent upon mechanism of resistance

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5051525354555657585960


Send appropriate cultures including blood

cultures and image as appropriate. Early post-

transplantation, healthcare-associated

infections including surgical site infections are

common.

Empiric Antibiotics

• Drug should be appropriate for suspected

source and local susceptibility patterns.

• Dose should be appropriate for patient’s body

habitus and creatinine clearance.

• In the setting of concern for MRSA consider

empiric vancomycin 15 mg/kg

• In the setting of multidrug-resistant Gram-

negative pathogens consider adding a second

agent (e.g., aminoglycoside or polymyxins)

until susceptibilities are available especially in

the setting of severe sepsis or shock. The

choice should be based on commonly isolated

pathogens and local antibiograms.

Suspected Bacterial Infection

Cultures negative after 48

hours

Cultures positive

• Narrow antibiotic regimen based

on antibiotic susceptibilities.

• Discontinue agents added

empirically that are duplicative in

spectrum or cover organisms not

detected in cultures.

• Convert parenteral agents to oral

if amenable based on patient’s

oral intake and drug

bioavailability.

• Discontinue* therapy based on

patient’s clinical improvement

rather than arbitrarily prescribing

a course.

*Minimal data on duration exists in LTR and antibiotic prescribing should be based on individual

patient characteristics (immunosuppression, source control, response etc.)

• De-escalate or discontinue

antibiotics (discontinue

broad-spectrum agents if

cultures unrevealing).

Source Control

• Remove central venous catheters and

urinary catheters as appropriate

• Drain abscesses and collections if

amenable

Page 29 of 35




Documents

Jonathan Hand, MD1404165/UQ404165_OA.pdf · Jonathan Hand, MD1 Gopi Patel, MD MS2* *Corresponding Author 1 Jonathan Hand, MD Department of Infectious Diseases Ochsner Clinic Foundation