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Treatment of multidrug-resistant Gram-negative skin and soft tissue

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 REVIEW

CURRENT
OPINION Treatment of multidrug-resistant Gram-negative
skin and soft tissue infections
Jean-Francois Jabbour a,, Sima L. Sharara b,, and Souha S. Kanj a

Purpose of review
The increase in skin and soft tissue infections (SSTI) because of multidrug-resistant (MDR) pathogens is a
global concern. Although MDR Gram-negative bacteria (GNB) are often overlooked as a cause of SSTIs,
their burden on the morbidity of many subgroups of patients is high. There is a paucity in the available
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treatment options and guidelines on how to treat these pathogens. This manuscript reviews the
management of SSTIs caused by carbapenem-resistant Enterobacteriaceae (CRE), Pseudomonas aeruginosa
(CRPA), Acinetobacter baumannii (CRAB), and Stenotrophomonas maltophilia. We also highlight a few
novel antibiotics that show promise in the future management of MDR-GNB SSTIs.
Recent findings
Studies on treatment options of MDR-GNB SSTIs are scarce. Most clinical trials investigating new antibiotics
have addressed conditions such as complicated intraabdominal infections, complicated urinary infections, and
respiratory infections. CREs are a heterogenous group of pathogens with various mechanisms of resistance
dictating susceptibility to different antimicrobial agents. Ceftazidime–avibactam, and meropenem–vaborbactam
have potent activity against some of the CREs, especially Klebsiella pneumoniae carbapenemase (KPC)
producers. Several novel antibiotics have potent activity against CRPA SSTIs, such as ceftazidime–avibactam,
ceftolozane–tazobactam, cefiderocol, delafloxacin, finafloxacin, and murepavadin. Cefiderocol may also play
an important role in the management of CRAB SSTIs, along with plazomicin and eravacycline.
Summary
MDR-GNB play a major role in SSTIs in patients with underlying immunodeficiency, as well as burn or
trauma-related injuries. With the alarming global rise in MDR-GNB resistance, antibiotic therapy for SSTIs
is challenging and must be guided by in-vitro susceptibility results. Currently, data extrapolated from other
indications and combination therapy can be used empirically pending microbiological data and
susceptibilities. Novel antibiotics are currently under development. It is hoped that future clinical trials will
be designed to address MDR-GNB SSTIs.
Keywords
Gram-negative bacteria, multidrug resistance, skin and soft tissue infections, therapy

INTRODUCTION 2014, result in a reduction of treatment failure rates

Multidrug resistance (MDR) in Gram-negative bacte-
ria (GNB) causing serious infections is a global prob-
lem and a major cause of morbidity and mortality
&
[1 ]. SSTIs caused by MDR-GNB are increasingly
seen in clinical practice, especially in patients with
diabetes mellitus, severe and chronic infections,
immunosuppression, prolonged hospitalization,
&
and following traumatic and war injuries [1 ,2].
Table 1 summarizes the patients at risk for MDR-
GNB SSTI and the most likely infecting pathogens.
The rise of resistance limits the options for effec-
tive treatment of SSTIs caused by MDR-GNB. Guide-
lines for SSTI treatment are set by many societies, and
adherence to these recommendations, such as those
set by the Infectious Diseases Society of America in
[3]. All current guidelines, however, have failed to
include specific recommendations on the directed
a
Division of Infectious Diseases, Department of Internal Medicine, Ameri-
can University of Beirut Medical Center, Beirut, Lebanon and bDivision of
Infectious Diseases, Department of Medicine, Johns Hopkins School of
Medicine, Baltimore, Maryland, USA
Correspondence to Souha S. Kanj, Division of Infectious Diseases,
Department of Internal Medicine, American University of Beirut Medical
Center, PO Box 11-0236, Riad El Solh 2020, 1107 Beirut, Lebanon.
Tel: +961 3 835 845; e-mail: sk11@aub.edu.lb

Jean-Francois Jabbour and Sima L. Sharara contributed equally to the
writing of this article.
Curr Opin Infect Dis 2020, 33:146–154
DOI:10.1097/QCO.0000000000000635

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 Treatment of resistant Gram-negative skin infections Jabbour et al.

antimicrobial therapy against MDR-GNB causing

KEY POINTS SSTIs. This review highlights the role of MDR-GNB
 MDR-GNB play an important role in SSTIs and current in SSTIs and offers an update on the suggested current
guidelines poorly address proper treatment options. treatment options. Duration of therapy will not be
specifically addressed, as this is highly dependent on
 Empiric combination therapy against suspected MDR- the underlying host, extent of disease, surgical
GNB causing SSTIs should be started early and
debridement, and response to therapy.
individualized based on the patient’s history and
antibiotic exposure, local epidemiology, and the
resistance rates of the unit to which the patient
is admitted. EMPIRIC MANAGEMENT OF SKIN AND
SOFT TISSUE INFECTIONS CAUSED BY
 Ceftazidime–avibactam, meropenem–vaborbactam, MULTIDRUG-RESISTANT GRAM-NEGATIVE
and imipenem/cilastatin–relebactam have potent BACTERIA
activity against CREs, especially KPC producers, and
can be used in combination with other agents or novel Prompt initiation of proper antimicrobial therapy is
agents, such as cefiderocol, eravacycline, and crucial for improving clinical outcomes in various
plazomicin, whereas for MBL-producing CREs, infectious diseases, and delays can result in an
aztreonam–avibactam is the favored drug of choice. increase in mortality [4]. Patients at risk for SSTI
 CRPA SSTIs can be treated with ceftazidime– with an MDR pathogen should be managed early
avibactam, ceftolozane–tazobactam, imipenem– with debridement when indicated, broad-spectrum
relebactam, and novel agents, such as delafloxacin, antimicrobial coverage, and wound care [5]. There
finafloxacin, and murepavadin. are no clear recommendations for the empiric ther-
apy of SSTIs caused by MDR-GNB. The recently
 Treatment of CRAB SSTIs includes a polymyxin
backbone in combination with carbapenems, updated 2018 guidelines of the World Society of
cefiderocol, or eravacycline. Emergency Surgery (WSES) and the Surgical Infec-
tion Society Europe (SIS-E) for the management
of SSTIs suggest in most cases coverage against

Table 1. Description of skin and soft tissue infections, associated Gram-negative pathogens, and patient risk factors
Common Gram-negative microbial
Type of infection Description pathogens Population at risk

Echthyma Cutaneous infection that causes hemorrhagic pustules and Pseudomonas spp., Stenotrophomonas Immunocompromised, malignancy,
gangrenosum evolves into a necrotic ulcer maltophilia, Enterobacteriaceae critically ill
Cellulitis Acute infection of the skin and subcutaneous tissue that results in Pseudomonas aeroginosa, Previous antibiotic exposure,
erythema, warmth, swelling and tenderness, with possible Enterobacteriaceae prolonged hospitalization
bullae or systemic symptoms (leukocytosis, fever)
Cellulitis in special Cellulitis, can present with ulceration, myonecrosis or Aeromonas spp. Traumatic freshwater injury, cirrhosis,
situations rhabdomyolysis diabetes, immunocompromised
Mild cellulitis, can progress rapidly with bullae, severe Vibrio vulnificus Traumatic injury with saltwater, shellfish,
myonecrosis, or nectrotizing fasciitis in high-risk individuals or fish, cirrhosis, hereditary
hemochromatosis, diabetes
Cellulitis with possible cutaneous abscesses Enterobacteriaceae, Pseudomonas Intravenous drug use
aeroginosa, usually polymicrobial
Metastatic cellulitis – tender, erythematous, warm subcutaneous S. maltophilia Immunocompromised, catheter and
infiltrates that can be well demarcated device placement
Necrotizing fasciitis Rapidly progressive inflammation of the fascia, with secondary Polymicrobial (Enterobacteriaceae, More common in abdomen or groin
necrosis of the subcutaneous tissue characterized by erythema, Pseudomonas aeroginosa) (Fournier’s gangrene), diabetes,
fever and pain out of proportion to skin manifestations obseity, or immunodeficiency
Diabetic foot infections Differentiated from uninfected ulcer, usually warm, Polymicrobial (Enterobacteriaceae, Uncontrolled diabetes, peripheral
erythematous, swollen, increasing exudate or pus, Pseudomonas spp.) vascular disease, chronic wounds,
inflammatory changes within ulcer bed, could include pain antibiotic exposure
or systemic signs (fever, leukocytosis)
Infected pressure ulcers Differentiated from uninfected ulcer, could present with new or Polymicrobial (Pseudomonas spp., Patients in long-term facilities or
worsening pain, clinical signs of fever and inflammation Enterobacteriaceae commonly prolonged hospital stay
Proteus mirabilis, Acinetobacter spp.)
Surgical site infections Infection of a surgical site with signs of erythema, Enterobacteriaceae, Acinetobacter, Operations on the axilla,
inflammation, pain, purulent drainage, possible systemic Pseudomonas spp. gastrointestinal tract, perineum, or
symptoms (fever, leukocytosis) female genital tract
Burn wound infection May be difficult to distinguish burn wound infection from Pseudomonas spp., S.maltophilia, Severe burn injury, prior antibiotic
noninfectious burn erythema, can be confirmed with tissue Acenitobacter spp., exposure, Gram-negative
biopsy Enterobacteriaceae colonization
Injury in war Increasing pain, erythema, or discharge from the wound, can Pseudomonas spp., A. baumannii, Chronic war traumatic wounds,
be associated with systemtic symptoms (fever, hemodynamic Enterobacteriaceae embedded foreign material
instability)

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Skin and soft tissue infections

Methicillin-Resistant Staphyloccocus aureus (MRSA) Other Enterobacteriaceae (CRACKLE-1) encompassed

but do not address GNB coverage [6]. Therefore,
considerations for appropriate empiric therapy
against MDR-GNB should rely on the patient’s his-
tory, risk factors, and prior antibiotic exposure, as
well as the local epidemiology of the country and
hospital, and - most importantly - the unit in which
the patient is managed. There is not a single agent
currently available that provides adequate coverage
for the four most troublesome MDR-GNB, therefore,
empiric coverage mostly relies on a combination of
two to three drugs pending identification, suscepti-
bility testing, and in some cases molecular typing, of
the offending organisms.
Early escalation/de-escalation to a targeted ther-
apy is of paramount importance in line with stew-
ardship efforts (Fig. 1).
MANAGEMENT OF SKIN AND SOFT
TISSUE INFECTION BY CARBAPENEM-
a cohort of 142 patients with a documented CRE
skin or soft tissue culture and found that the most
common wound type with CRE infection or coloni-
zation were pressure ulcers (34%) and surgical site
infections (30%) [8]. Patients who were admitted
from long-term care facilities were more prone to
CRE SSTIs and were less likely to undergo
surgical debridement.
Treatment of SSTIs in patients who had a long
course of antibiotics prior to hospitalization, admis-
sion from a long-term facility, pressure ulcers,
wounds in the lower extremities, abdomen or peri-
neum, and a history of diabetes mellitus require
coverage for CRE [9]. In view of the limited data
on the management of MDR-GNB SSTIs, physicians
often rely on combination therapy or therapy with
novel antibiotics.
Tigecycline has an excellent activity against
CREs and CRAB and can be used at a high dose or
in combination to achieve a good response [10 ].
&&

RESISTANT ENTEROBACTERIACEAE When novel antibiotics are not available, the

The frequency of CRE in SSTIs is estimated to be extended infusion of carbapenems can be used
around 1% [7]. The Consortium on Resistance when the minimal inhibitory concentration (MIC)
Against Carbapenem in Klebsiella pneumoniae and is 8 mg/l or less.

FIGURE 1. Algorithm for the management of multidrug resistant Gram-negative skin and soft tissue infections. CRAB,
carbapenem-resistant Acinetobacter baumannii; CRE, carbapenem-resistant Enterobacteriaceae; CRPA, carbapenem-resistant
Pseudomonas aeruginosa; GNB, Gram-negative bacteria; KPC, Klebsiella pneumoniae carbapenemase producers; MBL,
metallo-b-lactamase; MDR, multidrug-resistant; SM, Stenotrophomonas maltophilia; SSTI, skin and soft tissue infection; TMP-
SMX, trimethoprim–sulfamethoxazole.

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 Treatment of resistant Gram-negative skin infections Jabbour et al.

Table 2. Activity of novel antibiotic agents against multidrug-resistant Gram-negative pathogens

Novel antibiotic agent Activity against MDR organisms

CRE KPC CRE MBL CRE OXA CRPA CRAB SM

Aztreonam–avibactam þþ þþa þþ   þþ
Cefiderocol þþ þþ þþ þþ þþ þþ
Ceftaroline fosamil–avibactam þþ  þþ   
Ceftazidime–avibactam þþ  þþ þþ  
Ceftolozane–tazobactam    þþb  þ
Eravacycline þþ þþ þþ  þþ þþ
Imipenem/cilastatin–relebactam þþ  þc þþ  
Meropenem–vaborbactam þþ     
Murepavadin    þþ  
Plazomicin þþ þd þe þ þ 

–, No activity or intrinsic or acquired resistance; þ, good activity; þþ, excellent and potent activity. CRAB, carbapenem-resistant Acinetobacter baumannii;
CRE, carbapenem-resistant Enterobacteriaceae; CRPA, carbapenem-resistant Pseudomonas aeruginosa; KPC, Klebsiella pneumoniae carbapenemase producers;
MBL, metallo-b-lactamase; MDR, multidrug-resistant; SM, Stenotrophomonas maltophilia.
a
Activity diminished against certain Escherichia coli New Delhi Metallo-b-lactamase (NDM) isolates (attributed to novel insertion in PBP3).
b
Decreased activity for carbapenemase-producing strains of CRPA.
c
Mixed studies show that relebactam might weakly potentiate the activity of imipenem against OXA-type CREs.
d
Active against producers of Verona integron-encoded metallo-b-lactamase (VIM) and imipenemase (IMP). Not active against NDM primarily because of
coproduction of ribosomal methyltransferase enzymes.
e
Active against OXA-type CREs but increased resistance is observed mainly because of 16rRNA methyltransferases.

Ceftazidime–avibactam was found in the mechanisms of b-lactamases [14]. A large study

REPRISE trial to be effective in the treatment of
MDR-GNB when compared with the best available
therapy (BAT) [11]. Three hundred and seventeen
out of the 333 enrolled patients had CRE infections,
mostly complicated urinary tract infections (cUTIs)
and complicated intraabdominal infections (cIAIs),
and ceftazidime–avibactam was found to be effec-
tive, especially when the mechanism of resistance is
KPC or OXA-48 production. Table 2 summarizes the
activity of novel antibiotics, such as ceftazidime–
avibactam, on multidrug-resistant organisms.
Polymyxins have activity against both KPC and
MBL-producing CREs. Recent observational studies
demonstrated an improvement in the clinical suc-
cess rates and an added benefit with the addition of
carbapenems to polymyxins in the management
of KPC and VIM-producing CRE [12]. Due to the
recent increase in polymyxin resistance, epidemio-
logical patterns should tailor second-line therapies
in combining polymyxins with a carbapenem, tige-
cycline, or aminoglycoside. A recent study demon-
strated that the combination of polymyxin B and
ceftazidime–avibactam was successful in the treat-
ment of polymyxin B heretoresistant K. pneumoniae
in vitro [13].
Cefiderocol is a novel cephalosporin conjugated
with a catechol siderophore on its side chain.
It is active against all classes of b-lactamases, includ-
ing KPC and OXA-producers, and MBLs. Its
characteristically efficient cell entry and stability
to b-lactamase hydrolysis allows it to overcome all
demonstrated potent in-vitro activity and an inhi-
bition of 96% of clinical isolates of CRE, MDR
A. baumannii, MDR P. aeruginosa, Stenotrophomonas
maltophilia, and Burkholderia cepacia [15].
Eravacycline is a synthetic fluorocycline antibi-
otic that inhibits bacterial protein synthesis by bind-
ing to the 30S ribosomal subunit, and covers a broad
range of GNB including MDR E. coli, K. pneumoniae,
A. baumannii, and Bacteroides spp. It is superior to
tetracyclines in its increased potency in vitro, fewer
&
drug interactions, and good activity in biofilm [16 ].
The Investigating Gram-Negative Infections Treated
with Eravacycline (IGNITE1) trial compared erava-
cycline to ertapenem in the management of cIAI
and showed noninferiority to ertapenem and potent
activity against MDR Enterobacteriaceae [17]. The
IGNITE4 trial showed noninferiority to meropenem
with a clinical cure rate of 87.5% in patients with
&&
MDR Enterobacteriaceae cIAI [18 ]. IGNITE2 and
IGNITE3 compared oral and intravenous eravacy-
cline to levofloxacin in the treatment of cUTIs but
have both failed to result in noninferiority to date
(ClinicalTrials.gov identifiers NCT01978938 and
NCT03032510).
Plazomicin is a next-generation semisynthetic
aminoglycoside that inhibits bacterial protein syn-
thesis. Contrary to traditional aminoglycosides, it
evades aminoglycoside-modifying enzymes (AMEs),
and provides effective activity against Enterobacter-
iaceae, including CREs [19–23]. Plazomycin was
approved by the Federal and Drug Administration

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Skin and soft tissue infections
(FDA) for the management of cUTI in June 2018. A
trial examined plazomicin versus colistin in patients
with CRE infection combined with meropenem or
tigecycline [24]. Although the study was prema-
turely terminated because of low enrollment, pre-
liminary findings indicated that plazomicin was
associated with a reduced all-cause mortality at
28 days compared with colistin for CRE bloodstream
infections and with a safer adverse effect profile [24].
A recent study found plazomicin to be active against
CRE isolates from SSTI [25], but robust trials are
required to contextualize the therapeutic role of this
agent in SSTIs.
MANAGEMENT OF SKIN AND SOFT
TISSUE INFECTION BY KLEBSIELLA
PNEUMONIAE CARBAPENEMASE-
PRODUCING CARBAPENEM-RESISTANT
ENTEROBACTERIACEAE
The favored drug of choice for SSTIs with KPC-
producing CREs is ceftazidime–avibactam given that
the MIC 8 mg/l or less [26,27]. Compared with colis-
tin, ceftazidime–avibactam was shown to have a
lower all-cause 30-day hospital mortality and a bet-
ter outcome at 30-day disposition [26]. Although
relatively infrequent, resistance to ceftazidime–
avibactam is being observed, with rates up to
3.7% in China [28]. There are no current guidelines
for ceftazidime–avibactam-resistant CRE SSTI treat-
ment, but combination therapy with meropenem
was found to be effective [29].
Other antibiotics that can be used for KPC-pro-
ducing CREs include the prolonged infusion of
agents, such as meropenem–vaborbactam, imipe-
nem/cilastatin–relebactam, or polymyxins. The
recent TANGO II randomized trial, which investi-
gated the efficacy and safety of meropenem–vabor-
bactam versus BAT for CRE infections showed that
meropenem–vaborbactam significantly improved
clinical cure rates and had lower nephrotoxicity risk
and mortality compared with BAT [30]. However,
this trial did not include CRE SSTIs, had a small
sample size, and the data and safety monitoring
board advised to stop randomization to the BAT
arm as it was resulting in high risks. In vitro, mer-
openem–vaborbactam was very active against 99.5%
of KPC producers [31].
Relebactam is a novel b-lactamase inhibitor
related to avibactam that has been combined with
imipenem/cilastatin to provide effective activity to
class A and C b-lactamases [32]. Imipenem/cilasta-
tin-relebactam has demonstrated potent antimicro-
bial activity against KPC-producers, in vitro and
in vivo [33–36]. A trial comparing imipenem/
relebactam to colistin and imipenem in patients
150 www.co-infectiousdiseases.com
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
with imipenem-nonsusceptible bacterial infections
found that imipenem/relebactam resulted in higher
clinical response rates and lower 28-day mortality
compared with colistin, although the study
&
was not powered for statistical inference [37 ]. As
of July 2019, the FDA approved the use of imipe-
nem/cilastatin-relebactam for adults with cUTI and
cIAI wherever limited or no alternative treatment
options are available.
Ceftaroline fosamil–avibactam has an extended
activity to infections caused by Enterobacteriaceae,
including strains producing extended spectrum
beta-lactamases, KPC, or AmpC [33,38]. Ceftaroline
fosamil has been specifically studied in the context
of SSTI (mainly for its anti-staphylococcal activity)
[39,40], yet there have not been any studies exam-
ining the combination with avibactam in the man-
agement of MDR-GNB SSTIs.
Intravenous fosfomycin can also be an alterna-
tive agent for the treatment of select cases of KPC
infections, although studies on SSTIs are scarce. Due
to this drug’s high predisposition to confer resistance,
it is always recommended that fosfomycin be used in
combination with either tigecycline or colistin [41].
The combination of fosfomycin with colistin was
shown to result in an improved microbiological
response in bacteremia and respiratory infections,
&&
but there was no effect on survival [10 ].
MANAGEMENT OF SKIN AND SOFT
TISSUE INFECTION BY METALLO-BETA-
LACTAMASE-PRODUCING CARBAPENEM-
RESISTANT ENTEROBACTERIACEAE
An intrinsic resistance is conferred to b-lactam anti-
biotics for NDM producers, except for aztreonam.
Avibactam does not possess the ability to inhibit
&
MBL Class B and many Class D enzymes [16 ]. Hence,
the combination of ceftazidime–avibactam and
aztreonam was investigated and found to be syner-
gistic [42] and safe [43] in most cases of NDM-CREs.
The combination of aztreonam–avibactam pro-
tects aztreonam from hydrolysis and provides syn-
ergy in antimicrobial activity against multiple b-
lactamase-expressing strains with a wide MIC range
[44]. In-vitro studies have shown that aztreonam-
avibactam was highly active against all CRE strains
(KPC, OXA-48, MBL) and MDR strains [45–47], but
showed diminished activity against some Escherichia
coli isolates, which harbor an amino-acid insertion
in PBP3 [47,48]. An ongoing multicenter phase 3
clinical trial is assessing the safety and tolerability of
aztreonam–avibactam with metronidazole to mer-
openem and colistin for cIAI (ClinicalTrials.gov
Identifier: NCT03329092). A similar phase 3 trial
is examining aztreonam–avibactam compared with
Volume 33  Number 2  April 2020
 Treatment of resistant Gram-negative skin infections Jabbour et al.
BAT for hospitalized patients with infections includ-
ing cIAI, cUTI, nosocomial pneumonia and blood-
stream infections with MBL-producing GNB
(ClinicalTrials.gov Identifier: NCT03580044). The
results of these studies could provide insight into
the role of aztreonam–avibactam in the manage-
ment of MDR-GNB infections, although its use in
SSTIs remains unknown.
MANAGEMENT OF SKIN AND SOFT
TISSUE INFECTION BY CARBAPENEM-
RESISTANT PSEUDOMONAS
AERUGINOSA
Pseudomonas aeruginosa is a known cause of many
dermatologic manifestations, including severe and
even fatal infections such as ecthyma gangrenosum
and burn wound infections. CRPA is a serious and
growing pathogen and is mostly seen in neutropenic
cancer patients. Risk factors for acquiring CRPA
infections includes a prolonged hospitalization
and intensive care unit stay, diabetes mellitus,
and prior surgery. The strongest predictors for CRPA
infection are history of CRPA infection, tracheos-
tomy, and carbapenem use within 30 days [49].
A suitable option for the treatment of CRPA SSTIs
is ceftazidime–avibactam or ceftolozane–tazobac-
tam. The INFORM Surveillance Program identified
that 98.7% of CRPA SSTI isolates were susceptible to
ceftazidime–avibactam in the United States [7] and
that ceftazidime–avibactam and ceftolozane–tazo-
bactam were the most active compounds against
P. aeruginosa after colistin [50]. For CRPA isolates,
however, their susceptibility rates to both drugs
dropped by 27 and 21%, respectively, whereas colis-
tin retained a susceptibility rate of 99% [50]. Resis-
tance to ceftazidime mostly occurs through AmpC
induction and resistance to both antibiotics simulta-
neously was because of AmpD mutations [51].
Although these studies were not directly related to
SSTIs, it would be appropriate to test the susceptibil-
ity of CRPA isolates against ceftazidime–avibactam
and ceftolozane–tazobactam and initiate treatment
whenever possible. If found to be resistant, polymyx-
ins are an indispensable alternative, despite their
nephrotoxicity and ototoxicity.
Imipenem–relebactam has excellent activity
against CRPA because of the ability of relebactam
to inhibit the imipenem-hydrolyzing AmpC
enzymes and evade the up-regulated efflux pumps
[34–36,52,53].
Cefiderocol was found to have the strongest
activity against MDR P. aeruginosa strains when
compared with other antipseudomonal agents. It
was shown to be more potent in vitro compared
with ceftazidime–avibactam and ceftolozane–
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Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
&
tazobactam [54 ]. Delafloxacin and finafloxacin
are novel fluoroquinolones that exhibit antipseudo-
monal activity. Delafloxacin received FDA approval
in June 2017 for the treatment of acute SSTIs and
was found to be noninferior to other antibacterial
agents against MRSA and P. aeruginosa in phase 3
trials [55,56].
Murepavadin, a first-in-class antibiotic targeting
outer membrane proteins, was shown to be very
potent against CRPA, as well as ceftolozane–tazo-
bactam-resistant and colistin–resistant strains. This
agent retained potent in-vitro activity against MDR
and extensively drug-resistant strains of P. aerugi-
nosa and was four-to-eight-folds more active than
polymyxins [57,58]. There were two clinical trials
investigating murepavadin’s safety and efficacy in
respiratory infections that were prematurely termi-
nated because of the high rates of renal failures in
the murepavadin arm (ClinicalTrials.gov identifiers
NCT02096315 and NCT02096328). A topical formu-
lation of the drug is currently being developed and
may have a promising role in the future of CRPA
&
SSTI treatment [54 ].
MANAGEMENT OF CARBAPENEM-
RESISTANT ACINETOBACTER BAUMANNII
SKIN AND SOFT TISSUE INFECTIONS
CRAB can cause complicated SSTIs in the setting of
burns or combat-related wounds, as well as in
patients with morbid obesity, cirrhosis, immuno-
suppression, and diabetes mellitus [59,60]. A. bau-
mannii has a number of resistance mechanisms
including all four classes of b-lactamases, AMEs,
and efflux pumps [61]. CRAB is associated with a
significantly higher risk of mortality than patients
with carbapenem-susceptible isolates, which is in
part because of the inappropriate antimicrobial
treatment [62].
Despite the diminishing antibacterial options
for CRAB SSTIs, there are no specific guidelines for
their management. The first-line agents are poly-
myxins; however, colistin-resistant A. baummanii
can be found in as high as 50% of CRAB [63,64].
Tetracyclines, such as minocycline and tigecycline,
have been used [65], although rising resistance and
increased mortality associated with tigecycline have
made it a last resort option for CRAB [66].
Combination therapy in the management of
CRAB was shown to improve patient outcomes in
some clinical studies [67–70]. However, a recent
randomized controlled trial (RCT) showed that
monotherapy with colistin was noninferior to
a combination therapy with a carbapenem and
colistin with regard to mortality in severe CRAB
infections [71]. Moreover, a subgroup analysis of
www.co-infectiousdiseases.com 151
Skin and soft tissue infections
colistin-resistant CRAB isolates in this study found
that the colistin–meropenem arm was associated
with a higher mortality compared with the colistin
arm [72]. Another recent study of CRAB bacteremia
found that the combined therapy with high-dose
colistin and standard-dose tigecycline was not asso-
ciated with a reduction in mortality compared to
colistin monotherapy [73]. However, the use of colis-
tin results in challenges including renal toxicity,
difficulty achieving adequate and consistent plasma
levels, and rising resistance rates, which emphasize
the need for alternative therapeutic options [66].
Cefiderocol is likely to be the first new agent
active against CRAB that is expected to be approved
for clinical use [74,75]. A study on cUTIs showed
noninferiority of intravenous cefiderocol to imipe-
nem–cilastatin in patients with MDR-GNB infections
[14] and another found that it exhibited more potent
in vitro activity than ceftolozane–tazobactam and
&
ceftazidime–avibactam against CRAB [76 ].
Other novel agents include eravacycline, which
has shown in-vitro activity against tetracycline-
resistant A. baumannii isolates, with limited activity
against isolates expressing the efflux pump AdeABC.
A recent study found that the addition of sulbactam
to cefoperazone could increase the in-vitro antibac-
terial activity against CRAB [77]. Lastly, plazomicin
may play a role in combination therapy with carba-
penems against CRAB [78].
MANAGEMENT OF STENOTROPHOMONAS
MALTOPHILIA SKIN AND SOFT TISSUE
INFECTION
Stenotrophomonas maltophilia can cause heteroge-
neous manifestations of SSTI including cellulitis,
mucocutaneous ulcers, nonhealing limb and digit
ulcers, multifocal purpura and metastatic cellulitis
&
associated with catheter use [1 ,79]. S. maltophilia
infection is mostly seen in immunocompromised
patients, patients with chronic pulmonary infec-
tions, and critically ill patients [80,81]. Mortality
rates associated with S. maltophilia infection have
been estimated to be as high as 38% [82], with even
higher rates among immunocompromised patients
[83,84].
S. maltophilia is intrinsically resistant to carba-
penems and has become increasingly resistant to
many other broad-spectrum antimicrobial agents,
including b-lactams, trimethoprim/sulfamethoxa-
zole (TMP-SMX), fluoroquinolones and aminogly-
cosides [66,85,86]. Current therapy of choice for
SSTI includes high-dose TMP-SMX as monotherapy
when susceptible, or combination, with ceftazi-
dime, ticarcillin–clavulanate, tetracyclines, and flu-
oroquinolones, or with combinations or each other,
152 www.co-infectiousdiseases.com
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
with varying success [80]. Most of the novel antibi-
otic agents in clinical trials are not active against S.
maltophilia [32]. Aztreonam–avibactam has been
shown to be active against select clinical strains of
S. maltophilia in vitro [87] as avibactam overcomes
aztreonam resistance [87].
CONCLUSION
MDR-GNB plays an important role in SSTIs in immu-
nocompromised and at-risk patients. These infec-
tions are associated with high morbidity and
prolonged hospital stay. Recently released drugs
have shown potent activity against these MDR
pathogens, however, their role in the treatment of
SSTIs has not been shown in RCTs. In practice, their
use has been based on in-vitro susceptibility data
and efficacy data extrapolated from their efficacy in
other infection sites. With the complexity of the
molecular types of MDR-GNB, especially CRE, rapid
diagnostic molecular studies are needed to guide
therapy.
Various new agents show promise in the treat-
ment of MDR-GNB SSTIs. Clear guidelines on choices
of therapy and proper dosing for the directed therapy
against MDR-GNB SSTIs are needed. Beyond antibi-
otic management, anecdotal reports of other modal-
ities of treatment such a phage therapy, antimicrobial
peptides, and antibiotic nanotherapy show promis-
ing results in the management of challenging MDR
infections.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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Volume 33  Number 2  April 2020