Clinical Microbiology and Infection 28 (2022) 465e469
Contents lists available at ScienceDirect
Clinical Microbiology and Infection
journal homepage: www.clinicalmicrobiologyandinfection.com
Commentary
IDSA guidance and ESCMID guidelines: complementary approaches
toward a care standard for MDR Gram-negative infections
Alexander Lawandi 1, Christina Yek 1, 2, Sameer S. Kadri 1, *
1)
Critical Care Medicine Department, National Institutes of Health Clinical Center, Bethesda, MD, USA
2)
Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, Rockville, MD, USA
a r t i c l e i n f o
Article history:
Received 8 January 2022
Received in revised form
28 January 2022
Accepted 30 January 2022
Available online 9 February 2022
Editor: L Leibovici
Antimicrobial resistance continues to pose a major global threat
[1]. In response, a number of new antibiotics have been developed
and approved for use over the last few years. However, more often
than not, the clinical trial evidence base supporting these new
drugs has only cursorily involved the treatment of infections due to
multidrug resistant (MDR) pathogens [2]. As such, clinicians
treating complex MDR Gram-negative infections have to decide
between using potentially toxic, yet time-honoured agents and
newer, potentially safer agents substantiated by less generalizable
evidence. In response to this problem, an expert panel of the Eu-
ropean Society of Clinical Microbiology and Infectious Diseases
(ESCMID) was convened to complete a systematic review of the
published literature and compile a practice guideline to support
clinicians in the selection of appropriate antimicrobial regimens
against commonly encountered MDR Gram-negative pathogens.
In this issue of Clinical Microbiology and Infection, the panel of-
fers recommendations on the treatment of third-generation ceph-
alosporin-resistant Enterobacterales (3GCephRE), carbapenem-
resistant Enterobacterales (CRE), carbapenem-resistant Pseudo-
monas aeruginosa, and carbapenem-resistant Acinetobacter bau-
manii [3]. These four phenotypes were selected based on their
classification as critical priority pathogens by the WHO owing to
their high disease burden and few treatment options available or in
* Corresponding author. Sameer S. Kadri, National Institutes of Health Clinical
Center, Critical Care Medicine Department, Bethesda, MD 20892, USA.
E-mail address: sameer.kadri@nih.gov (S.S. Kadri).
DOI of original article: https://doi.org/10.1016/j.cmi.2021.11.025.
https://doi.org/10.1016/j.cmi.2022.01.030
1198-743X/© 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
development [1]. This guideline complements recent expert guid-
ance [4,5] from the Infectious Diseases Society of America (IDSA),
whose expert panel provided recommendations on the treatment
of extended-spectrum b-lactamase-producing Enterobacterales
(ESBL-E), AmpC b-lactamase-producing Enterobacterales (AmpC-
E), P. aeruginosa with difficult-to-treat resistance, carbapenem-
resistant A. baumanii, and Stenotrophomonas maltophilia.
The natural reaction for those familiar with recent IDSA guidance
might be: “what’s new and different in the new ESCMID guideline?”,
and when differences exist, “which recommendations should one
follow?” Thankfully, the recommendations in the ESCMID guideline
and IDSA guidance are generally consistent across several in-
dications (Table 1). Nonetheless, they diverge in some key areas
(Table 2), highlighting differences in drug availability between the
United States and Europe (e.g. intravenous formulations of fosfo-
mycin and amoxicillin-clavulanate are available in Europe but not in
the United States), the uncertainties prevailing in the field, and the
conspicuous paucity of comparative effectiveness trials. Under-
standing where and why they diverge might help prescribers navi-
gating murky waters make more informed antibiotic selections.
Perhaps the most noteworthy discrepancy between the ESCMID
and IDSA guidelines is the recommended role of piperacillin-
tazobactam in the treatment of third-generation cephalosporin-
resistant Enterobacterales, which the IDSA categorizes according to
resistance mechanism (ESBL-E), whereas ESCMID, perhaps more
pragmatically, identifies solely on phenotypic resistance
(3GCEphRE). Importantly, for patients with severe infections (e.g.
sepsis and septic shock), regardless of the source, both panels agree
that there is no role for targeted piperacillin-tazobactam upfront
based on the current literature. However, whereas the IDSA panel
recommends against its use even for nonsevere infections other
than uncomplicated cystitis caused by ESBL-E, the ESCMID panel
suggests it would be an acceptable first-line therapy in select, low-
inoculum, nonsevere, 3GCephRE infections, and even as a step-
down therapy for severe infections.
Why the discrepancy? Simply, the lens used to analyze the risk
vs. benefit of using carbapenems for every 3GCephRE infection. The
MERINO trial [6] is arguably the bedrock underlying the shared
recommendation to use carbapenems over piperacillin-tazobactam
for severe infection associated with 3GCephRE isolates susceptible
466 A. Lawandi et al. / Clinical Microbiology and Infection 28 (2022) 465e469

Table 1
Key similarities between the European Society of Clinical Microbiology and Infectious Diseases and Infectious Diseases Society of America expert panel recommendations on
the treatment of multidrug resistant Gram-negative pathogens

European Society of Clinical Microbiology and Infectious Infectious Diseases Society of America
Diseases

Empiric therapy Not addressed Not addressed

3GCephRE/ESBL-E
Initial therapy for severe infection due to
3GCephRE/ESBL-E
Antimicrobial stewardship to minimize use
of carbapenems for 3GCephRE/ESBL-E
when possible
Role of cefepime for 3GCephRE/ESBL-E
Carbapenem-resistant Enterobacterales
Recommended therapy for nonsevere
carbapenem-resistant Enterobacterales
infections
Recommended therapy for metallo-b-
lactamase producers
Role of tigecycline
Role of combination therapy outside of
metallo-b-lactamase producers
Pseudomonas aeruginosa with
difficult-to-treat resistance
Role of combination (targeted) therapy
CRAB
Antibiotic of choice for CRAB with isolate
showing sulbactam susceptibility
Antibiotic of choice for CRAB with isolate
showing sulbactam resistance
Use/choice of combination therapy for
severe CRAB infections
Carbapenems (mero- or imipenem; ertapenem if no
septic shock)
Consider use of old b-lactam/b-lactamase inhibitors or
quinolones for low-risk, nonsevere infections or as step-
down therapy; use of quinolones, trimethoprim-
sulfamethoxazole for step-down therapy; use of
aminoglycosides or intravenous fosfomycin for
complicated UTI without septic shock
Conditional recommendation against use
Consider use of old antibiotic with in vitro activity
Cefiderocol is conditionally recommended; treatment
with combined ceftazidime-avibactam with aztreonam
suggested within section on combination therapy
Tigecycline should not be used in the treatment of
bloodstream infections and hospital-acquired/
ventilator-associated pneumonia
Not routinely recommended if treated with preferred
regimen
Insufficient evidence to routinely recommend for or
against
Ampicillin-sulbactam (alternatives include polymyxins,
high-dose tigecycline if active in vitro)
No recommendations (consider use of polymyxin or
high-dose tigecycline if active in vitro)
Combination therapy with at least two active agents
(polymyxins, aminoglycosides, tigecycline, sulbactam,
extended-infusion carbapenem (if meropenem MIC <8
mg/L) combinations); avoid polymyxin-meropenem or
polymyxin-rifampin combinations
Carbapenems
Use of quinolones, trimethoprim-sulfamethoxazole for
complicated UTI or as oral step-down therapy for
infection outside the urinary tract if appropriate criteria
met; use of nitrofurantoin and trimethoprim-
sulfamethoxazole for cystitis (can also consider
amoxicillin-clavulanate, single-dose aminoglycosides,
oral fosfomycin, piperacillin-tazobactam if prior
improvement demonstrated)
Cefepime should be avoided even if in vitro
susceptibility demonstrated, unless for cystitis if clinical
improvement
Specific agents recommended include quinolones,
trimethazole-sulfamethoxazole, single-dose
aminoglycoside
Both ceftazidime-avibactam with aztreonam or
cefiderocol monotherapy are preferred treatment
options
Tigecycline use should be avoided for noneintra-
abdominal infections
Not routinely recommended if treated with preferred
regimen
Not routinely recommended; if no preferred regimen
has in vitro activity, addition of aminoglycoside with
in vitro activity to preferred regimen can be considered
Ampicillin-sulbactam (alternatives include
tetracyclines, polymyxins, cefiderocol)
No recommendations (consider use of high-dose
ampicillin-sulbactam and addition of a second active
agent)
Combination therapy of at least two active agents
(including tetracyclines, polymyxins, extended-infusion
meropenem, cefiderocol), including high-dose
ampicillin-sulbactam as component of therapy; avoid
fosfomycin and rifampin as part of combination
therapy, avoid polymyxin-meropenem combinations
without third agent

3GCephRE, third-generation cephalosporin-resistant Enterobacterales; CRAB, carbapenem-resistant Acinetobacter baumanii; ESBL-E, extended-spectrum b-lactamase-pro-
ducing Enterobacterales; UTI, urinary tract infection

to these agents in vitro. The study failed to demonstrate non-
inferiority of piperacillin-tazobactam compared with meropenem
for patients with ceftriaxone-resistant Escherichia coli or Klebsiella
pneumoniae bloodstream infection, respectively. This finding was
further supported by the meropenem (vs. piperacillin-tazobactam)
group being disadvantaged with higher baseline APACHE II scores
and longer time to appropriate antibiotics at baseline, and the
majority of deaths in the piperacillin-tazobactam group were pre-
ceded by (and likely associated with) clinical and microbiologic
failure.
Unreliable MIC results, coharbouring multiple b-lactamases (e.g.
with coexpression of OXA-1), and the inoculum effect have been
proposed to explain the reduced efficacy of old b-lactam/b-lacta-
mase inhibitors (BL/BLIs) against 3GCephRE [7]. These factors likely
influenced IDSA guidance recommending against their use for
ESBL-E. On the flipside, in a post hoc analysis of the MERINO trial,
broth microdilution identified a higher proportion of isolates
nonsusceptible to piperacillin-tazobactam than originally reported
based on other methods; when these were excluded, the mortality
benefit in the meropenem group was attenuated and no longer
statistically significant [8]. Furthermore, the early termination of
the trial before achieving the prespecified planned enrolment and
the fact that piperacillin-tazobactam was not administered as
prolonged infusions raises the “what if” question.
The ESCMID guidelines express concern that unrestrained car-
bapenem use for nonsevere infections may further drive carbape-
nem resistance and that the limitations of the MERINO trial design
and its anchoring on bloodstream infection reduce both internal
validity and generalizability to nonsevere infections. In support of
its position, the ESCMID panel relies on a number of small obser-
vational studies with moderate-high risk of bias showing non-
inferior outcomes when piperacillin-tazobactam is used compared
with carbapenems (see Table 3 of the ESCMID guideline [3]). Both
positions have their rationale: Larger ongoing clinical trials,
including those specifically planned to address these controversial
issues (e.g. PETER-PEN), might offer additional insight and are
eagerly awaited. Other key differences between the IDSA guidance
and ESCMID guideline can be found in Table 2.
 A. Lawandi et al. / Clinical Microbiology and Infection 28 (2022) 465e469 467

Table 2
Key differences between the European Society of Clinical Microbiology and Infectious Diseases and Infectious Diseases Society of America expert panel recommendations on
the treatment of multidrug resistant Gram-negative pathogens

European Society of Clinical Microbiology and Infectious Diseases Society of America

Infectious Diseases

Methodology used in guidance development
Uncomplicated cystitis
3GCephRE/ESBL-E/AmpC producers
Use of old b-lactam/b-lactamase inhibitors for
3GCephRE/ESBL-E
Choice of noneb-lactam antibiotics for 3GCephRE/
ESBL-E complicated UTI without sepsis/ septic shock
Treatment of organisms with moderate to high
likelihood of AmpC b-lactamase production due to
inducible ampC gene (e.g. Enterobacter cloacae,
Citrobacter freundii)
Carbapenem-resistant Enterobacterales
Recommended therapy for severe infection
Recommended therapy for complicated UTI
Role of eravacycline
Role of carbapenems in combination therapy
Pseudomonas aeruginosa with difficult-to-treat resistance
Recommended therapy for severe infections
Recommended therapy for low-risk, nonsevere
infection
Combination therapy if preferred regimen not active
in vitro
CRAB
Preferred tetracycline derivative for CRAB
Cefiderocol for CRAB
Stenotrophomonas maltophilia
Systematic review of literature with evidence
classified using GRADE
Not specifically addressed
Consider piperacillin-tazobactam or
amoxicillin-clavulanic acid for low-risk,
nonsevere infections (UTI or biliary infection
after source control, without sepsis/septic
shock) or as step-down therapy after patients
are stabilized
Recommend short courses of aminoglycosides
when active in vitro, intravenous fosfomycin, or
trimethoprim-sulfamethoxazole
No recommendations
Conditional recommendation for ceftazidime-
avibactam or meropenem-vaborbactam; no
recommendation for imipenem-relebactam or
cefiderocol
Aminoglycosides, including plazomicin,
recommended over tigecycline
No evidence for use of eravacycline
Not recommended unless MIC is <8 mg/L, in
which case high-dose extended infusion could
be used in conjunction with other agents
(provided preferred regimen not an option)
Suggest ceftolozane-tazobactam if active
in vitro; insufficient evidence for cefiderocol,
imipenem-relebactam, or ceftazidime-
avibactam
Use of old antibiotics with in vitro activity
recommended
Polymyxin, aminoglycoside, or fosfomycin
should be used in combination with second
in vitro active agent (no combination
specifically recommended)
Recommend high-dose tigecycline; do not
include minocycline. State need for more data
on eravacycline
Conditionally recommend against use citing
lack of data
Not addressed
Nonsystematic review of literature coupled
with clinical experience of panellists
Recommendations according to pathogen
Recommend avoiding initiation of piperacillin-
tazobactam even if in vitro susceptibility is
demonstrated. Allow for use of amoxicillin-
clavulanic acid or continuation of piperacillin-
tazobactam for cystitis if clinical improvement
Recommend trimethoprim-sulfamethoxazole
and fluoroquinolones. Do not include
aminoglycosides and recommend against oral
Fosfomycin, but do not include intravenous
fosfomycin
Recommend cefepime, carbapenems,
trimethoprim-sulfamethoxazole,
fluoroquinolones, or nitrofurantoin or single-
dose aminoglycosides (for cystitis) depending
on antibiotic susceptibility
Recommended preferred regimen could include
ceftazidime-avibactam, meropenem-
vaborbactam, imipenem-relebactam, or
cefiderocol for UTI
Preferred regimen includes ceftazidime-
avibactam, meropenem-vaborbactam,
imipenem-relebactam, or cefiderocol
Acceptable in treatment of intra-abdominal
infections; use should be avoided for other sites
of infection
Not addressed
Suggest ceftolozane-tazobactam, imipenem-
relebactam, ceftazidime-avibactam as
monotherapy; cefiderocol if within urinary tract
Suggest ceftolozane-tazobactam, imipenem-
relebactam, ceftazidime-avibactam, or single-
dose of aminoglycoside for uncomplicated
cystitis
Aminoglycoside combined with new b-lactam/
b-lactamase inhibitors with MIC closest to
breakpoint recommended
Preferentially recommend minocycline, with
high-dose tigecycline as an alternative. State
need for more data on eravacycline and
omadacycline
Limit recommendations to treatment of CRAB
infections refractory to other antibiotics or
where intolerance precludes their use
Addressed with specific recommendations

3GCephRE, third-generation cephalosporin-resistant Enterobacterales; CRAB, carbapenem-resistant Acinetobacter baumanii; ESBL-E, extended-spectrum b-lactamase-pro-
ducing Enterobacterales, UTI, urinary tract infection

In their recommendations, both societies emphasize the impor-
tance of stewardship in their own way. For example, IDSA suggests
using extended-infusion meropenem for ertapenem-resistant, mer-
openem-susceptible CRE infections outside of the urinary tract
(unless the pathogen is identified as a carbapenemase producer) and
reserving ceftazidime-avibactam for CRE resistant to all carbape-
nems. The ESCMID panel emphasizes that novel agents should be
spared in the treatment of nonsevere infections. This is an important
paradigm, particularly for the new BL/BLIs, because there is concern
regarding resistance developing with their excessive use [9].
Restricting them to targeted therapy for severe infections might be
critical. That said, ceftazidime-avibactam has already been found to
be used empirically as much as 25% of the time [10], and neither the
IDSA nor the ESCMID guidance addresses empiric therapy. Recog-
nizing the importance of timely appropriate therapy in the outcomes
of these infections while balancing stewardship considerations
should mandate a nuanced discussion on the role of novel agents in
the empiric therapy of patients with risk factors for MDR organisms.
468 A. Lawandi et al. / Clinical Microbiology and Infection 28 (2022) 465e469
One must contextualize the disparate recommendations consid-
ering the fundamental differences between guidance and guidelines
and the circumstances surrounding their development. The IDSA
guidance documents emerged at a time when there were no author-
itative Gram-negative practice guidelines and the uptake of newly
introduced Gram-negative active antibiotics (over existing relatively
toxic alternatives) had been languid [10]. Urgency trumped protracted
systematic review; the focus was streamlined to a few key pathogens
and questions with a focus on managing patients with antibiotic op-
tions available in the United States. There was more room to accom-
modate treatment experience and expert opinion and generate
hypotheses in the absence of hard clinical data. However, in an area
where guidance is desperately sought, a single available approach
might be treated as incontrovertible evidence, which is not optimal,
especially given that the data are still scarce. On the other hand, sys-
tematic selection and pooling of studies, strict reliance on the GRADE
methodology to qualify recommendations, and a stronger emphasis on
prioritization of antibiotic stewardship has led the ESCMID guidelines
to remain systematic, thorough, and conservative, but caused the panel
to remain silent on many key bugedrug combinations and scenarios.
Perhaps there is utility in having both approaches; a rapidly updatable,
expert opinion-heavy option and a comprehensive and systematic
approach could coexist and occupy unique niches, offer complemen-
tary approaches, and keep the other in check.
Most importantly, this dual approach empowers clinicians to
compare and debate recommendations and assimilate them with
prior knowledge and individual case specifics to augment their
management decisions. Of note, no quantitative or meta-analyses
were performed in preparing the ESCMID guideline, which is un-
derstandable given the degree of heterogeneity in the populations
studied and the definitions and methods applied across studies. Yet,
careful consideration was given to the risk of bias. Fifty-eight
percent (13 of 24) of the recommendations by ESCMID were
based on low- to very low-graded evidence. For context, this is not
far from what was reported for the evidence base in the recent
Clostridoides difficile management guidelines, in which 61% (14 of
23) of recommendations were based on low- to very low-graded
evidence [11]. Nevertheless, caveat emptor. With less evidence
comes more responsibility; clinicians, trialists, and regulators will
need to pay particular attention to emerging evidence and the
uptake and impact of these respective recommendations in the real
world.
What is made clear in both the ESCMID guidelines and IDSA
guidance is the remarkable paucity of head-to-head trials
comparing therapies directed against Gram-negative pathogens
resistant to all first-line, highly safe, and effective antibiotics.
Clinical trials in this field face many hurdles. The low prevalence of
difficult-to-treat antibiotic resistant, Gram-negative infections in
some developed countries, where clinical trials are disproportion-
ately centred [12e14], consequent slow patient accrual [15], diffi-
culties in establishing standard-of-care comparator arms among
participating centres [16], and the high costs of trials studying
investigational therapies [17] collectively limit the undertaking of
randomized trials desperately needed to inform care.
Unfortunately there are no quick fixes to these problems. As a
result, much of the data used are still observational and/or repre-
sent comparisons of investigational agents to best-available ther-
apy, which itself varies across studies [18,19]. Heterogeneity in the
best-available therapy within and across studies weakens the
conclusions that can be drawn from many of the comparative
effectiveness studies underpinning the recommendations. In that
vein, the consistencies observed between the IDSA and ESCMID
recommendations might, in fact, lead to greater uniformity over
time in the usual care of MDR Gram-negative infections and pave
the way for more standard comparator arms for future trials. Future
iterations of the IDSA and ESCMID guidelines should include how
clinicians might approach empiric therapy selection. There is an
urgent need to understand the utility and trade-offs of leveraging
BL/BLIs as empiric therapy in patients with suspected infection or
sepsis with a high likelihood of a resistant pathogen to inform
future versions of these recommendations. Continued analysis of
large real-world databases might offer insights, such as the number
needed to treat and high-risk groups that could inform future
region-specific empiric therapy guidelines. Infectious disease so-
cieties could lead this initiative; insights gained might also inform
future updates to sepsis guidelines.
In summary, the ESCMID committee has performed a compre-
hensive summary of the available literature regarding the treat-
ment of four important pathogen phenotypes and is a laudable
attempt at providing clinical guidance despite limitations within
the body of available evidence. Combined with the recommenda-
tions from the IDSA, these guidelines will prove to be an invaluable
resource for clinicians facing complex MDR Gram-negative in-
fections. Perhaps most importantly, the work of these panels may
help harmonize practice and improve trial design, and continue to
shed light on where more effort (and study) is needed.
Transparency declaration
The authors have no conflict of interest to declare. This work was
supported, in part, by the Intramural Research Program of the Na-
tional Institutes of Health Clinical Center and the National Institute
of Allergy and Infectious Diseases. The comments are those of the
authors, and do not necessarily represent the official position of the
National Institutes of Health or the U.S. Government.
Author contributions
All authors contributed equally to the conceptualization, writing
of the original draft, and reviewing and editing of this work.
References
[1] Tacconelli E, Carrara E, Savoldi A, Harbarth S, Mendelson M, Monnet DL, et al.
Discovery, research, and development of new antibiotics: The WHO priority
list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis 2018;18:
318e27.
[2] de Kraker MEA, Sommer H, de Velde F, Gravestock I, Weiss E, McAleenan A,
et al. Optimizing the design and analysis of clinical trials for antibacterials
against multidrug-resistant organisms: A white paper from COMBACTE's
STAT-Net. Clin Infect Dis 2018;67:1922e31.
[3] Paul M, Carrara E, Retamar P, Ta €ngden T, Bitterman R, Bonomo RA, et al. Euro-
pean Society of Clinical Microbiology and Infectious Diseases (ESCMID) guide-
lines for the treatment of infections caused by multidrug-resistant Gram-
negative bacilli (endorsed by European Society of Intensive Care Medicine). Clin
Microbiol Infect 2022;28:521e47.
[4] Tamma PD, Aitken SL, Bonomo RA, Mathers AJ, van Duin D, Clancy CJ. Infec-
tious Diseases Society of America guidance on the treatment of AmpC b-lac-
tamase-producing Enterobacterales, carbapenem-resistant Acinetobacter
baumannii, and Stenotrophomonas maltophilia infections. Available at: https://
www.idsociety.org/practice-guideline/amr-guidance/. [Accessed 4 January
2022].
[5] Tamma PD, Aitken SL, Bonomo RA, Mathers AJ, van Duin D, Clancy CJ. Infec-
tious Diseases Society of America antimicrobial-resistant treatment guidance:
Gram-negative bacterial infections. Available at: https://www.idsociety.org/
practice-guideline/amr-guidance/. [Accessed 4 January 2022].
[6] Harris PNA, Tambyah PA, Lye DC, Mo Y, Lee TH, Yilmaz M, et al. Effect of
piperacillin-tazobactam vs meropenem on 30-day mortality for patients with
E. coli or Klebsiella pneumoniae bloodstream infection and ceftriaxone resis-
tance: A randomized clinical trial. JAMA 2018;320:984e94.
[7] Villegas MV, Esparza G, Reyes J. Should ceftriaxone-resistant Enter-
obacterales be tested for ESBLs? A PRO/CON debate. JAC Antimicrob Resist
2021;3:dlab035.
[8] Henderson A, Paterson DL, Chatfield MD, Tambyah PA, Lye DC, De PP,
et al. Association between minimum inhibitory concentration, beta-
lactamase genes and mortality for patients treated with piperacillin/
tazobactam or meropenem from the MERINO study. Clin Infect Dis
2021;73:e3842e50.
 A. Lawandi et al. / Clinical Microbiology and Infection 28 (2022) 465e469
[9] Shields RK, Chen L, Cheng S, Chavda KD, Press EG, Snyder A, et al.
Emergence of ceftazidime-avibactam resistance due to plasmid-borne
bla(KPC-3) mutations during treatment of carbapenem-resistant Klebsi-
ella pneumoniae infections. Antimicrob Agents Chemother 2017;61:
e02097e116.
[10] Strich JR, Ricotta E, Warner S, Lai YL, Demirkale CY, Hohmann SF, et al.
Pharmacoepidemiology of ceftazidime-avibactam use: A retrospective cohort
analysis of 210 U.S. hospitals. Clin Infect Dis 2020;72:611e21.
[11] van Prehn J, Reigadas E, Vogelzang EH, Bouza E, Hristea A, Guery B, et al.
European Society of Clinical Microbiology and Infectious Diseases: 2021 up-
date on the treatment guidance document for Clostridioides difficile infection
in adults. Clin Microbiol Infect 2021;27:S1e21.
[12] Kadri SS, Adjemian J, Lai YL, Spaulding AB, Ricotta E, Prevots DR, et al.
Difficult-to-treat resistance in Gram-negative bacteremia at 173 U.S.
hospitals: Retrospective cohort analysis of prevalence, predictors, and
outcome of resistance to all first-line agents. Clin Infect Dis 2018;67:
1803e14.
[13] Kadri SS, Lai YL, Ricotta EE, Strich JR, Babiker A, Rhee C, et al. External vali-
dation of difficult-to-treat resistance prevalence and mortality risk in Gram-
negative bloodstream infection using electronic health record data from 140
U.S. hospitals. Open Forum Infect Dis 2019;6:ofz110.
469
[14] Strich JR, Warner S, Lai YL, Demirkale CY, Powers 3rd JH, Danner RL, et al.
Needs assessment for novel Gram-negative antibiotics in U.S. hospitals: A
retrospective cohort study. Lancet Infect Dis 2020;20:1172e81.
[15] McKinnell JA, Dwyer JP, Talbot GH, Connolly LE, Friedland I, Smith A, et al.
Plazomicin for infections caused by carbapenem-resistant Enterobacteriaceae.
N Engl J Med 2019;380:791e3.
[16] Infectious Diseases Society of America. White paper: Recommendations on
the conduct of superiority and organism-specific clinical trials of antibacterial
agents for the treatment of infections caused by drug-resistant bacterial
pathogens. Clin Infect Dis 2012;55:1031e46.
[17] Towse A, Hoyle CK, Goodall J, Hirsch M, Mestre-Ferrandiz J, Rex JH. Time for a
change in how new antibiotics are reimbursed: Development of an insurance
framework for funding new antibiotics based on a policy of risk mitigation.
Health Policy 2017;121:1025e30.
[18] Alraddadi BM, Saeedi M, Qutub M, Alshukairi A, Hassanien A, Wali G. Efficacy
of ceftazidime-avibactam in the treatment of infections due to carbapenem-
resistant Enterobacteriaceae. BMC Infect Dis 2019;19:772.
[19] Shields RK, Nguyen MH, Chen L, Press EG, Potoski BA, Marini RV, et al. Cef-
tazidime-avibactam is superior to other treatment regimens against
carbapenem-resistant Klebsiella pneumoniae bacteremia. Antimicrob Agents
Chemother 2017;61. e00883e17.