Treatment of ESBL, CRE and Pseudomonas

Clinical Infectious Diseases
I D S A F E AT U R E S
Infectious Diseases Society of America Guidance on the

Treatment of Extended-Spectrum β-lactamase Producing
Enterobacterales (ESBL-E), Carbapenem-Resistant
Enterobacterales (CRE), and Pseudomonas aeruginosa with
Difficult-to-Treat Resistance
(DTR-P. aeruginosa)
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Pranita D. Tamma,1 Samuel L. Aitken,2 Robert A. Bonomo,3 Amy J. Mathers,4 David van Duin,5 and Cornelius J. Clancy6
1
Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA, 2Division of Pharmacy, The University of Texas MD Anderson Cancer Center, Houston, Texas,
USA, 3Medical Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, University Hospitals Cleveland Medical Center and Departments of Medicine, Pharmacology,
Molecular Biology, and Microbiology, Case Western Reserve University, Cleveland, Ohio, USA, 4Departments of Medicine and Pathology, University of Virginia, Charlottesville, Virginia, USA,
5
Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA, and 6Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
Background. Antimicrobial-resistant infections are commonly encountered in US hospitals and result in significant morbidity
and mortality. This guidance document provides recommendations for the treatment of infections caused by extended-spectrum
β-lactamase–producing Enterobacterales (ESBL-E), carbapenem-resistant Enterobacterales (CRE), and Pseudomonas aeruginosa
with difficult-to-treat resistance (DTR-P. aeruginosa).
Methods. A panel of 6 infectious diseases specialists with expertise in managing antimicrobial-resistant infections formulated
common questions regarding the treatment of ESBL-E, CRE, and DTR-P. aeruginosa infections. Based on review of the published litera-
ture and clinical experience, the panel provide recommendations and associated rationale for each recommendation. Because of significant
differences in the molecular epidemiology of resistance and the availability of specific anti-infective agents globally, this document focuses
on treatment of antimicrobial-resistant infections in the United States.
Results. Approaches to empiric treatment selection, duration of therapy, and other management considerations are briefly dis-
cussed. The majority of guidance focuses on preferred and alternative treatment recommendations for antimicrobial-resistant in-
fections, assuming that the causative organism has been identified and antibiotic susceptibility testing results are known. Treatment
recommendations apply to both adults and children.
Conclusions. The field of antimicrobial resistance is dynamic and rapidly evolving, and the treatment of antimicrobial-resistant
infections will continue to challenge clinicians. This guidance document is current as of 17 September 2020. Updates to this guid-
ance document will occur periodically as new data emerge. Furthermore, the panel will expand recommendations to include other
problematic gram-negative pathogens in future versions. The most current version of the guidance including the date of publication
can be found at www.idsociety.org/practice-guideline/amr-guidance/.
Keywords. ESBL; CRE; Pseudomonas aeruginosa; MDRGN; antimicrobial resistance.
The rise in antimicrobial resistance (AMR) continues to be a Antibiotic Resistant Threats Report [2]. Although there has
global crisis [1, 2]. Collectively, antimicrobial-resistant patho- been an increase in the availability of novel antibiotics to
gens cause more than 2.8 million infections and more than combat resistant infections in recent years [3], resistance to a
35 000 deaths annually in the United States, according to number of these agents has been observed [4]. Three groups
the 2019 Centers for Disease Control and Prevention (CDC) of antimicrobial-resistant gram-negative bacteria pose partic-
ular therapeutic challenges: extended-spectrum β-lactamase–
producing Enterobacterales (ESBL-E), carbapenem-resistant
Received 23 September 2020; editorial decision 23 September 2020; published online Enterobacterales (CRE), and Pseudomonas aeruginosa with
27 October 2020.
Correspondence: P. D. Tamma, Department of Pediatrics, 200 North Wolfe St, Room 3149
difficult-to-treat resistance (DTR-P. aeruginosa) [5]. The CDC
Baltimore, MD 21287 (ptamma1@jhmi.edu). has designated these pathogens as urgent or serious threats [2].
Clinical Infectious Diseases® 2021;72(7):e169–83 They are encountered in US hospitals of all sizes and cause a
© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society
of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
wide range of serious infections that carry significant morbidity
DOI: 10.1093/cid/ciaa1478 and mortality. Treatment options against ESBL-E, CRE, and
AMR Treatment Guidance • cid 2021:72 (1 April) • e169

DTR-P. aeruginosa infections remain limited despite approval literature, coupled with clinical experience. Answers include
of new antibiotics. There is often uncertainty about the precise a brief discussion of the rationale that supports the recom-
role(s) of new agents in clinical practice [6–8]. mendations. For each pathogen group, a table is provided
The Infectious Diseases Society of America (IDSA) identified with preferred and alternative treatment recommendations,
the development and dissemination of clinical practice guide- after antimicrobial susceptibility data are known. Treatment
lines and guidance documents for clinicians as a top initiative in recommendations apply to both adult and pediatric popu-
its 2019 Strategic Plan [9]. IDSA acknowledged that the ability lations. Suggested antibiotic dosing for adult patients with
to address rapidly evolving topics such as AMR was limited by antimicrobial-resistant infections, assuming normal renal
prolonged timelines needed to generate new or updated clinical and hepatic function, is provided in Table 1.
practice guidelines. As an alternative and complement to com-
prehensive clinical practice guidelines, IDSA endorsed the de- GENERAL MANAGEMENT RECOMMENDATIONS
velopment of more narrowly focused guidance documents for
Preferred and alternative treatment recommendations in this
the treatment of specific infectious processes. Guidance docu-
guidance document assume that the causative organism has been
ments address specific clinical questions for difficult-to-manage

identified and in vitro activity of antibiotics has been demon-
infections that are not covered by present guidelines. The
strated. The panel did not consider the cost of agents. Assuming
documents are prepared by a small team of experts based on a
2 antibiotics are equally effective and safe, cost, convenience,
comprehensive (but not necessarily systematic) review of the lit-
and local formulary availability are important considerations in
erature. Additionally, such guidance documents do not include
selecting a specific agent. The panel recommends that infectious
a formal grading of the evidence, unlike IDSA guidelines that
diseases specialists be involved in the management of patients
use the GRADE (Grading of Recommendations Assessment,
with antimicrobial-resistant infections, if feasible.
Development, and Evaluation) framework. This guidance doc-
ument is current as of 17 September 2020. Updates to this Empiric Therapy
document will occur periodically as new data emerge. Future Empiric treatment recommendations are not provided in this guid-
iterations will also address other resistant pathogens. The most ance document since a given host at risk for infection by 1 of the
current version of the guidance including the date of publica- pathogen groups is usually at risk of infection by other antimicrobial-
tion can be found at www.idsociety.org/practice-guideline/ resistant pathogens. Empiric treatment decisions should be guided
amr-guidance/. by local susceptibility patterns for the most likely pathogens. When
The overarching goal of this document is to assist clin- determining empiric treatment for a given patient, clinicians should
icians, including those with and without infectious diseases consider previous organisms and associated antibiotic suscepti-
expertise, in selecting antibiotic therapy for infections caused bility data in the past 6 months and antibiotic exposures in the past
by ESBL-E, CRE, and DTR-P. aeruginosa. Although brief de- 30 days (eg, if a treatment course of piperacillin-tazobactam was
scriptions of notable clinical trials, resistance mechanisms, recently completed, consider empiric coverage with a gram-nega-
and susceptibility testing methods are included, this guid- tive agent from a different class that offers a comparable spectrum
ance is not meant to provide a comprehensive review of these of activity, such as meropenem). Empiric decisions should be re-
topics. This document is framed as answers to a series of clin- fined based on the severity of the patient’s illness, whether the pa-
ical questions, each of which can stand on its own. Because tient is immunocompromised, and the likely source of the infection
of significant differences in the molecular epidemiology of (eg, presumed ventilator-associated pneumonia typically warrants
resistance and availability of specific anti-infectives globally, broader empiric coverage than presumed cystitis).
this document focuses on treatment recommendations for
antimicrobial-resistant infections in the United States. Duration of Therapy
Recommendations on durations of therapy are not provided, but
clinicians are advised that prolonged treatment courses are not nec-
essary against infections by antimicrobial-resistant pathogens per se,
METHODOLOGY
compared with infections caused by the same bacterial species with a
This IDSA guidance document was developed by a panel of 6 more susceptible phenotype. After antibiotic susceptibility results are
actively practicing infectious diseases specialists with clinical available, it may become apparent that inactive antibiotic therapy was
and research expertise in the treatment of resistant bacte- initiated empirically. This may impact the duration of therapy. For
rial infections. Through a series of web-based meetings, the example, cystitis is typically a mild infection. If an antibiotic not ac-
panel developed several commonly encountered treatment tive against the causative organism was administered empirically for
questions and corresponding answers for each pathogen cystitis but clinical improvement nonetheless occurred, it is generally
group. They reached consensus on the recommendations not necessary to repeat a urine culture, change the antibiotic regimen,
for each question based on extensive review of the published or extend the planned treatment course [11]. However, for all other
e170 • cid 2021:72 (1 April) • Tamma et al

Table 1. Suggested Dosing of Antibiotics for the Treatment of Extended-spectrum β-Lactamase–Producing Enterobacterales, Carbapenem-resistant
Enterobacterales, and Pseudomonas aeruginosa With Difficult-to-Treat Resistance Infections
Agent Adult Dosage, Assuming Normal Renal and Liver Function
Amikacin Cystitis: 15 mg/kg/dosea IV once

All other infections: 20 mg/kg/dosea IV × 1 dose; subsequent doses and
dosing interval based on pharmacokinetic evaluation
Amoxicillin-clavulanate Cystitis: 875 mg (amoxicillin component) PO every 12 hours
Cefiderocol 2 g IV every 8 hours, infused over 3 hours
Ceftazidime-avibactam 2.5 g IV every 8 hours, infused over 3 hours
Ceftazidime-avibactam and aztreonam (infused together) Ceftazidime-avibactam: 2.5 g IV every 8 hours, infused over 3 hours
plus
Aztreonam: 2 g IV every 8 hours, infused over 3 hours
Ceftolozane-tazobactam Cystitis: 1.5 g IV every 8 hours, infused over 1 hour
All other infections: 3 g IV every 8 hours, infused over 3 hours
Ciprofloxacin 400 mg IV every 8 hours or 750 mg PO every 12 hours

Colistin Refer to international consensus guidelines on polymyxins10
Eravacycline 1 mg/kg/dose IV every 12 hours
Ertapenem 1 g IV every 24 hours, infused over 30 minutes
Fosfomycin Cystitis: 3 g PO × 1 dose
Gentamicin Cystitis: 5 mg/kg/dosea IV once
Imipenem-cilastatin Cystitis (standard infusion): 500 mg IV every 6 hours, infused over 30
minutes
All other infections (extended-infusion): 500 mg IV every 6 hours, infused
over 3 hours
Imipenem-cilastatin-relebactam 1.25 g IV every 6 hours, infused over 30 minutes
Levofloxacin 750 mg IV/PO every 24 hours
Meropenem Cystitis (standard infusion): 1 g IV every 8 hours
All other infections (extended-infusion): 2 g IV every 8 hours, infused over
3 hours
Meropenem-vaborbactam 4 g IV every 8 hours, infused over 3 hours
Nitrofurantoin Cystitis: macrocrystal/monohydrate (Macrobid®)100 mg PO every 12
hours
Cystitis: Oral suspension: 50 mg every 6 hours
Plazomicin Cystitis: 15 mg/kga IV × 1 dose
All other infections: 15 mg/kga IV × 1 dose; subsequent doses and dosing
interval based on pharmacokinetic evaluation
Polymyxin B Refer to international consensus guidelines on polymyxins10
Tigecycline Uncomplicated intra-abdominal infections (standard dose): 100 mg IV × 1
dose, then 50 mg IV every 12 hours
Complicated intra-abdominal infections (high dose): 200 mg IV × 1 dose,
then 100 mg IV every 12 hours
Tobramycin Cystitis: 7 mg/kg/dosea IV × 1 dose
Trimethoprim-sulfamethoxazole Cystitis: 160 mg (trimethoprim component) IV/PO every 12 hours
Other infections: 8–10 mg/kg/day (trimethoprim component) IV/PO divided
every 8–12 hours; maximum dose 320 mg PO every 8 hours
Abbreviations: IV, intravenous; PO, by mouth.
a
Recommend using adjusted body weight for patients >120% of ideal body weight for aminoglycoside dosing.
infections included in this document, if antibiotic susceptibility data EXTENDED-SPECTRUM β-LACTAMASE–PRODUCING

indicate a potentially inactive agent was initiated empirically, a change ENTEROBACTERALES
to an active regimen for a full treatment course (dated from the start The incidence of ESBL-E infections in the United States in-
of active therapy) is recommended. Additionally, important host fac- creased by 53% from 2012 through 2017, in large part due to
tors related to immune status, ability to attain source control, and ge- increased community-acquired infections [12]. ESBLs are
neral response to therapy should be considered when determining enzymes that inactivate most penicillins, cephalosporins,
treatment durations for antimicrobial-resistant infections, as with the and aztreonam. ESBL-E generally remain susceptible to
treatment of any bacterial infection. carbapenems. ESBLs do not inactivate non–β-lactam agents

(eg, ciprofloxacin, trimethoprim-sulfamethoxazole, genta- preserve their activity for future infections and to limit associ-
micin). However, organisms that carry ESBL genes often carry ated toxicities, particularly with the fluoroquinolones.
additional genes or mutations in genes that mediate resistance Amoxicillin-clavulanate, single-dose aminoglycosides, and
to a broad range of antibiotics. oral fosfomycin are alternative options for ESBL-E cystitis.
Any gram-negative organism has the potential to harbor Amoxicillin-clavulanate is an alternative rather than preferred
ESBL genes; however, they are most prevalent in Escherichia agent since randomized, controlled trial data have shown it is
coli, Klebsiella pneumoniae, Klebsiella oxytoca, and Proteus mi- associated with a higher clinical failure rate than ciprofloxacin
rabilis [13, 14]. CTX-M enzymes, particularly CTX-M-15, are for cystitis, presumably due to persistent vaginal bacterial col-
the most common ESBLs in the United States [14]. ESBLs other onization [22]. Aminoglycosides are nearly exclusively elimin-
than CTX-M with unique hydrolyzing abilities have been iden- ated by the renal route in their active form. A single intravenous
tified, including variants of narrow-spectrum TEM and SHV dose of an aminoglycoside is generally effective for cystitis, with
β-lactamases with amino acid substitutions [15–17]. Routine minimal toxicity, but robust trial data are lacking [23]. Oral
EBSL testing is not performed by most clinical microbiology la- fosfomycin is an alternative agent exclusively for treatment of
ESBL-producing E. coli cystitis as the fosA gene, intrinsic to

boratories [18, 19]. Rather, nonsusceptibility to ceftriaxone (ie,
ceftriaxone minimum inhibitory concentrations [MICs] ≥2 µg/ K. pneumoniae and several other gram-negative organisms,
mL), is often used as a proxy for ESBL production [19]. For can hydrolyze the drug and may lead to clinical failure [24, 25].
this guidance document, ESBL-E refers to presumed or con- Randomized, controlled trial data indicate that oral fosfomycin
firmed ESBL-producing E. coli, K. pneumoniae, K. oxytoca, or is associated with higher clinical failure than nitrofurantoin for
P. mirabilis. Table 2 outlines preferred and alternative treatment uncomplicated cystitis [20]. Doxycycline is not recommended
recommendations for ESBL-E infections. Treatment recom- for the treatment of ESBL-E cystitis due to its limited urinary
mendations for ESBL-E infections assume in vitro activity of excretion [26].
preferred and alternative antibiotics has been demonstrated.
Question 2: What are preferred antibiotics for the treat-
Question 1: What are preferred antibiotics for the treatment ment of pyelonephritis and complicated urinary tract infections
of uncomplicated cystitis caused by ESBL-E? (cUTIs) caused by ESBL-E?
Recommendation: Nitrofurantoin and trimethoprim- Recommendation: Ertapenem, meropenem, imipenem-
sulfamethoxazole are preferred treatment options for uncom- cilastatin, ciprofloxacin, levofloxacin, or trimethoprim-
plicated cystitis caused by ESBL-E. sulfamethoxazole are preferred treatment options for
Rationale: Nitrofurantoin and trimethoprim- pyelonephritis and cUTIs caused by ESBL-E.
sulfamethoxazole have been shown to be safe and effective op- Rationale: A cUTI is defined as a UTI that occurs in as-
tions for cystitis [11, 20, 21]. sociation with a structural or functional abnormality of
Although fluoroquinolones (ie, ciprofloxacin or levofloxacin) the genitourinary tract, or any UTI in a male patient.
and carbapenems are effective agents for ESBL-E cystitis, their Carbapenems, ciprofloxacin, levofloxacin, and trimethoprim-
usage for cystitis is discouraged when other safe and effective sulfamethoxazole are all preferred treatment options for pa-
options are available. Limiting use of these agents serves to both tients with ESBL-E pyelonephritis and cUTIs based on the
Table 2. Recommended Antibiotic Treatment Options for Presumed or Confirmed Extended-spectrum β-Lactamase–Producing Enterobacterales,
Assuming In Vitro Susceptibility to Agents in Table
Alternative Treatment if First-line

Source of Infection Preferred Treatment Options not Available or Tolerated
Cystitis Nitrofurantoin, trimethoprim-sulfamethoxazole Amoxicillin-clavulanate, single-dose

aminoglycosides, fosfomycin
(Escherichia coli only)
Ciprofloxacin, levofloxacin, ertapenem,
meropenem, imipenem-cilastatin
Pyelonephritis or com- Ertapenem, meropenem, imipenem-cilastatin, ciprofloxacin,
plicated urinary tract levofloxacin, or trimethoprim-sulfamethoxazole
infectiona
Infections outside of the Meropenem, imipenem-cilastatin, ertapenem
urinary tract
Oral step-down therapy to ciprofloxacin, levofloxacin, or
trimethoprim-sulfamethoxazole should be consideredb
a
A complicated urinary tract infection (UTI) is defined as a UTI that occurs in association with a structural or functional abnormality of the genitourinary tract, or any UTI in a male patient.
b
Oral step-down therapy can be considered after susceptibility to the oral agent is demonstrated, patients are afebrile and hemodynamically stable, appropriate source control is achieved,
and there are no issues with intestinal absorption.

ability of these agents to achieve high concentrations in susceptibility to piperacillin-tazobactam is demonstrated. If
the urine. If a carbapenem is initiated and susceptibility to piperacillin-tazobactam is initiated as empiric therapy for cys-
ciprofloxacin, levofloxacin, or trimethoprim-sulfamethoxazole titis caused by an organism later identified as an ESBL-E and
is demonstrated, transitioning to these agents is preferred over clinical improvement occurs, no change or extension of antibi-
completing a treatment course with a carbapenem. Limiting otic therapy is necessary.
carbapenem use in these situations will preserve their activity Rationale: Piperacillin-tazobactam demonstrates in vitro
for future antimicrobial-resistant infections. Nitrofurantoin activity against a number of ESBL-E [32]. However, a ran-
and oral fosfomycin do not achieve adequate concentrations domized, controlled trial of ESBL-E bloodstream infections
in the renal parenchyma and should be avoided if the upper indicated inferior results with piperacillin-tazobactam com-
urinary tract is infected [27, 28]. Doxycycline is not recom- pared with carbapenem therapy [29]. The effectiveness of
mended for the treatment of ESBL-E pyelonephritis or cUTIs piperacillin-tazobactam in the treatment of invasive ESBL-E
due to its limited urinary excretion [26]. infections may be diminished by the potential for organ-
Question 3: What are preferred antibiotics for the treatment isms to have increased expression of the ESBL enzyme or

of infections outside of the urinary tract caused by ESBL-E? by the presence of multiple β-lactamases [33]. Additionally,
Recommendation: A carbapenem is preferred for the treat- piperacillin-tazobactam MIC testing may be inaccurate and/
ment of infections outside of the urinary tract caused by ESBL-E. or poorly reproducible when ESBL enzymes are present
Rationale: A carbapenem is recommended as first-line [34–36].
treatment of infections outside of the urinary tract caused by Question 5: Is there a role for cefepime in the treatment of
ESBL-E, based largely on data from a multicenter, random- infections caused by ESBL-E when in vitro susceptibility to
ized, controlled trial [29]. In this trial, 30-day mortality was
cefepime is demonstrated?
reduced for patients with ESBL E. coli and K. pneumoniae
Recommendation: Cefepime should be avoided for the treat-
bloodstream infections treated with meropenem compared
ment of infections caused by ESBL-E, even if susceptibility to
with piperacillin-tazobactam [29]. Comparable clinical
cefepime is demonstrated. If cefepime is initiated as empiric
trial data are not available for infections of other body sites.
therapy for cystitis caused by an organism later identified as an
Nevertheless, the panel recommends extrapolating evidence
ESBL-E and clinical improvement occurs, no change or exten-
for ESBL-E bloodstream infections to other common sites of
sion of antibiotic therapy is necessary.
infection, namely, intra-abdominal infections, skin and soft
Rationale: Observational studies and a subgroup analysis of
tissue infections, and pneumonia.
23 patients in a randomized trial that compared cefepime and
The role of oral step-down therapy for ESBL-E infections
carbapenems for the treatment of invasive ESBL-E infections
outside of the urinary tract has not been formally evaluated.
demonstrated either no difference in outcomes or poorer out-
However, oral step-down therapy has been shown to be a reason-
comes with cefepime [37–40]. Cefepime MIC testing may be
able treatment consideration for Enterobacterales bloodstream
inaccurate and/or poorly reproducible when ESBL enzymes are
infections, including those caused by antimicrobial-resistant
isolates, after appropriate clinical milestones are achieved [30, present [34, 35, 41].
31]. Based on the known bioavailability and sustained serum Question 6: What are preferred antibiotics in the treatment
concentrations of oral fluoroquinolones and trimethoprim- of infections caused by E. coli, K. pneumoniae, K. oxytoca, or
sulfamethoxazole, these agents are reasonable treatment op- P. mirabilis not susceptible to ceftriaxone if confirmatory phe-
tions for patients with ESBL-E infections if susceptibility to notypic ESBL testing is negative?
the oral agent is demonstrated, patients are afebrile and hemo- Recommendation: Antibiotic treatment selection can be
dynamically stable, appropriate source control has occurred, based on susceptibility testing results if a locally validated ESBL
and there are no concerns with intestinal absorption. phenotypic test does not indicate ESBL production.
Clinicians should avoid oral step-down to nitrofurantoin, Rationale: Currently, there is no Clinical and Laboratory
fosfomycin, doxycycline, or amoxicillin-clavulanate for ESBL-E Standards Institute endorsed phenotypic method for confirma-
bloodstream infections. Nitrofurantoin and fosfomycin achieve tory ESBL testing [19]. For hospitals with clinical microbiology
poor serum concentrations. Amoxicillin-clavulanate and dox- laboratories that do not perform ESBL phenotypic testing, a
ycycline achieve unreliable serum concentrations. ceftriaxone MIC ≥2 µg/mL should be used as a proxy for ESBL
Question 4: Is there a role for piperacillin-tazobactam in the production by E. coli, K. pneumoniae, K. oxytoca, or P. mirabilis
treatment of infections caused by ESBL-E when in vitro suscep- [19]. Phenotypic tests (eg, double-disk synergy test, ETEST,
tibility to piperacillin-tazobactam is demonstrated? automated susceptibility platform algorithms) to exclude the
Recommendation: Piperacillin-tazobactam should be avoided possibility of ESBL production by clinical isolates should be
for the treatment of infections caused by ESBL-E, even if interpreted with caution. Results should be used for clinical

decision-making only after local laboratory validation of testing families (eg, differentiating a KPC from an OXA-48–like
[42, 43]. carbapenemase). There are several molecular platforms used in
US clinical microbiology laboratories to identify carbapenemase
Question 7: What is the preferred antibiotic for the treatment
genes (eg, Verigene Gram-Negative Blood Culture Test,
of bloodstream infections caused by ceftriaxone nonsusceptible
GenMark ePlex Blood Culture Identification Gram-negative
E. coli, K. pneumoniae, K. oxytoca, or P. mirabilis, if a blaCTX-M
Panel, BioFire FilmArray Blood Culture Identification Panels).
gene is not detected using a molecular platform that includes
Carbapenemase phenotypic and/or genotypic testing are not
this target?
performed by all clinical microbiology laboratories. Table 3
Recommendation: Carbapenem therapy is preferred if
outlines preferred and alternative treatment recommendations
a blaCTX-M gene is not detected in E. coli, K. pneumoniae,
for CRE infections. Treatment recommendations for CRE in-
K. oxytoca, or P. mirabilis isolates that are not susceptible to
fections assume in vitro activity of preferred and alternative
ceftriaxone since the absence of a blaCTX-M gene does not exclude
antibiotics has been demonstrated.
the presence of other ESBL genes.
Rationale: Commercially available molecular platforms for Question 1: What are preferred antibiotics for the treatment

β-lactamase gene detection from positive blood cultures (eg, of uncomplicated cystitis caused by CRE?
Verigene Gram-Negative Blood Culture Test, GenMark ePlex Recommendation: Ciprofloxacin, levofloxacin, trimethoprim-
Blood Culture Identification Gram-negative Panel) limit ESBL sulfamethoxazole, nitrofurantoin, or a single dose of an
detection to blaCTX-M genes. The absence of blaCTX-M genes in aminoglycoside are preferred treatment options for uncompli-
E. coli, K. pneumoniae, K. oxytoca, and P. mirabilis that are cated cystitis caused by CRE. Standard infusion meropenem is a
not susceptible to ceftriaxone (ie, ceftriaxone MIC ≥2 µg/mL) preferred treatment option for cystitis caused by CRE resistant to
does not exclude the presence of other ESBL genes (eg, blaSHV, ertapenem but susceptible to meropenem when carbapenemase
blaTEM ESBL variants). Therefore, carbapenem therapy is re- testing results are either not available or negative.
commended, at least initially. Rationale: Clinical trial data evaluating the efficacy of most pre-
ferred agents for CRE cystitis are not available. However, as these
agents achieve high concentrations in urine, they are expected
CARBAPENEM-RESISTANT ENTEROBACTERALES
to be effective for CRE cystitis when active. Some agents listed
CRE account for more than 13 000 nosocomial infections as alternative options for ESBL-E cystitis are recommended as
and contribute to more than 1000 deaths annually in the preferred agents for CRE cystitis. These agents are not preferred
United States [2]. The CDC defines CRE as members of the agents for the treatment of ESBL-E cystitis in order to preserve
Enterobacterales order resistant to at least 1 carbapenem anti- their activity for more invasive infections. They are, however, pre-
biotic or producing a carbapenemase enzyme [2]. A CRE iso- ferred agents for CRE cystitis because there are generally fewer
late may be resistant to some carbapenems (eg, ertapenem) but treatment options available for these infections.
not others (eg, meropenem). CRE comprise a heterogenous Aminoglycosides are almost exclusively eliminated by the
group of pathogens with multiple potential mechanisms of re- renal route in their active form. A single intravenous dose of an
sistance, broadly divided into those that are carbapenemase- aminoglycoside is generally effective for cystitis with minimal
producing and those that are not carbapenemase-producing. toxicity [23]. Individual aminoglycosides are equally effective if
Carbapenemase-producing isolates account for approximately susceptibility is demonstrated. In general, higher percentages of
half of all CRE infections in the United States [44–46]. The most CRE clinical isolates are susceptible to amikacin and plazomicin
common carbapenemases in the United States are Klebsiella than to other aminoglycosides [50, 51]. Plazomicin may remain
pneumoniae carbapenemases (KPCs), which can be produced active against isolates resistant to amikacin.
by any Enterobacterales. Other notable carbapenemases that Meropenem is a preferred agent against CRE cystitis for iso-
have been identified in the United States include New Delhi lates that remain susceptible to meropenem since most of these
metallo-β-lactamases (NDMs), Verona integron-encoded isolates do not produce carbapenemases [45]. Meropenem
metallo-β-lactamases (VIMs), imipenem-hydrolyzing metallo- should be avoided if carbapenemase testing is positive, even if
β-lactamases (IMPs), and oxacillinase (eg, OXA-48–like) susceptibility to meropenem is demonstrated.
carbapenemases [47, 48]. Knowledge of whether a CRE clin- If none of the preferred agents is active, ceftazidime-
ical isolate is carbapenemase-producing and, if it is, the specific avibactam, meropenem-vaborbactam, imipenem-cilastatin-
carbapenemase produced are important in guiding treatment relebactam, and cefiderocol are alternative options for CRE
decisions. cystitis [52–56]. Data are insufficient to favor one agent over the
Phenotypic tests such as the modified carbapenem in- others. Although a clinical trial suggested increased mortality
activation method and the Carba NP test can differentiate with cefiderocol compared with best available therapy against
carbapenemase and non-carbapenemase–producing CRE a variety of infections due to carbapenem-resistant gram-nega-
[49]. Molecular testing can identify specific carbapenemase tive bacteria, these findings do not appear to extend to urinary

Table 3. Recommended Antibiotic Treatment Options for Carbapenem-Resistant Enterobacterales, Assuming In Vitro Susceptibility to Agents in Table
Alternative Treatment if First-

line Options not Available or
Source of Infection Preferred Treatment Tolerated
Cystitis Ciprofloxacin, levofloxacin, trimethoprim- Ceftazidime-avibactam,

sulfamethoxazole, nitrofurantoin, or a meropenem-vaborbactam,
single dose of an aminoglycoside imipenem-cilastatin-
relebactam, and cefiderocol
Meropenema (standard infusion): only if Colistin (when no alternative
ertapenem-resistant, meropenem- options are available)
susceptible, AND carbapenemase
testing results are either not available
or negative
Pyelonephritis or complicated urinary tract infectionb Ceftazidime-avibactam, meropenem- Once-daily aminoglycosides
vaborbactam, imipenem-cilastatin-
relebactam, and cefiderocol
Meropenema (extended-infusion): only if

ertapenem-resistant, meropenem-
susceptible, AND carbapenemase
testing results are either not available
or negative
Infections outside of the urinary tract Meropenema (extended-infusion) Ceftazidime-avibactam
Resistant to ertapenem, susceptible to
meropenem, AND carbapenemase testing
results are either not available or negative
Infections outside of the urinary tract Ceftazidime-avibactam, meropenem- Cefiderocol
vaborbactam, and imipenem-cilastatin-
relebactam
Resistant to ertapenem, resistant to meropenem, AND Tigecycline, eravacycline
carbapenemase testing results are either not (generally limited to intra-
available or negative abdominal infections)
Klebsiella pneumoniae carbapenemases identified Ceftazidime-avibactam, meropenem- Cefiderocol
(or carbapenemase positive but identify of vaborbactam, imipenem-cilastatin-
carbapenemase unknownc) relebactam
Tigecycline, eravacycline
(generally limited to intra-
abdominal infections)
Metallo-β-lactamase (ie, NDM, VIM, IMP) Ceftazidime-avibactam + aztreonam, Tigecycline, eravacycline
carbapenemase identified cefiderocol (generally limited to intra-
OXA-48-like carbapenemase identified Ceftazidime-avibactam Cefiderocol
Tigecycline, eravacycline
(generally limited to intra-
a
The majority of infections caused by carbapenem-resistant Enterobacterales (CRE) resistant to ertapenem but susceptible to meropenem are caused by organisms that do not produce
carbapenemases.
b
c
The vast majority of carbapenemase-producing Enterobacterales infections in the United States are due to bacteria that produce Klebsiella pneumoniae carbapenemases (KPC). If a
disease-causing Enterobacterales is carbapenemase-producing but the specific carbapenemase enzyme is unknown, it is reasonable to treat as if the strain is a KPC producer. If a patient
is infected with a CRE strain with an unknown carbapenemase status and the patient has recently traveled from an area where metallo-β-lactamases are endemic (eg, Middle East, South
Asia, Mediterranean), treatment with ceftazidime-avibactam plus aztreonam or cefiderocol as monotherapy is recommended. Preferred treatment approaches for infections caused by
metallo-β-lactamase producers also provide activity against KPC and OXA (oxacillinase)-48-like enzymes.
tract infections [55, 57]. Fosfomycin use should be limited to of nephrotoxicity [58]. Polymyxin B should not be used as
E. coli cystitis as the fosA gene (intrinsic to certain gram-nega- treatment for CRE cystitis due to its predominantly nonrenal
tive organisms such as Klebsiella species, Enterobacter spp., and clearance [59].
Serratia marcescens) can hydrolyze fosfomycin and may lead to
clinical failure [24, 25]. Randomized, controlled trial data indi- Question 2: What are preferred antibiotics for the treat-
cate that oral fosfomycin is associated with higher clinical failure ment of pyelonephritis and complicated urinary tract infections
than nitrofurantoin for uncomplicated cystitis [20]. (cUTIs) caused by CRE?
Colistin is an alternative consideration for treating Recommendation: Ceftazidime-avibactam, meropenem-
CRE cystitis only if none of the above agents is an option. vaborbactam, imipenem-cilastatin-relebactam, and cefiderocol
Colistin converts to its active form in the urinary tract. are preferred treatment options for pyelonephritis and cUTIs
Clinicians should remain cognizant of the associated risk caused by CRE resistant to both ertapenem and meropenem.

Extended-infusion meropenem is a preferred treatment op- Ceftazidime-avibactam is an alternative treatment for
tion for pyelonephritis and cUTIs caused by CRE resistant to ertapenem-resistant, meropenem-susceptible CRE infections
ertapenem but susceptible to meropenem when carbapenemase outside of the urinary tract. However, the panel prefers to reserve
testing results are either not available or negative. ceftazidime-avibactam for the treatment of infections caused by
Rationale: A cUTI is defined as a UTI that occurs in as- CRE resistant to all carbapenems in order to preserve its activity.
sociation with a structural or functional abnormality of the When carbapenemase production is present, infections should be
genitourinary tract, or any UTI in a male patient. Ceftazidime- treated as if the causative organism is meropenem-resistant, re-
avibactam, meropenem-vaborbactam, imipenem-cilastatin- gardless of the meropenem MIC. The panel recommends against
relebactam, and cefiderocol are preferred treatment options the use of meropenem-vaborbactam or imipenem-cilastatin-
for pyelonephritis and cUTIs caused by CRE resistant to both relebactam to treat ertapenem-resistant, meropenem-susceptible
ertapenem and meropenem based on randomized, controlled infections caused by CRE since these agents do not offer any sig-
trials that show noninferiority of these agents to common com- nificant advantage beyond that of extended-infusion meropenem.
parator agents for UTIs [52–56]. Data are insufficient to favor
one agent over the others. Although a clinical trial suggested Question 4: What are the preferred antibiotics for the treat-

increased mortality with cefiderocol compared with best avail- ment of infections outside of the urinary tract caused by CRE re-
able therapy against a variety of infections due to carbapenem- sistant to both ertapenem and meropenem when carbapenemase
resistant gram-negative bacteria, these findings do not appear testing results are either not available or negative?
to extend to UTIs [55, 57]. Recommendation: Ceftazidime-avibactam, meropenem-
Extended-infusion meropenem is a preferred agent against vaborbactam, and imipenem-cilastatin-relebactam are the pre-
pyelonephritis and cUTIs caused by CRE that remain suscep- ferred treatment options for infections outside of the urinary tract
tible to meropenem since most of these isolates do not pro- caused by CRE resistant to both ertapenem and meropenem when
duce carbapenemases [45]. Meropenem should be avoided carbapenemase testing results are either not available or negative.
if carbapenemase testing is positive, even if susceptibility to Rationale: In the United States, the vast majority of infections
meropenem is demonstrated. caused by CRE resistant to both ertapenem and meropenem are
In patients in whom the potential for nephrotoxicity is caused by organisms that either do not produce carbapenemases
deemed acceptable, once-daily aminoglycosides for a full treat- or by organisms that produce KPC-carbapenemases [45].
ment course is an alternative option. Once-daily plazomicin was Ceftazidime-avibactam, meropenem-vaborbactam, and
noninferior to meropenem in a randomized, controlled trial imipenem-cilastatin-relebactam are preferred treatment op-
that included patients with pyelonephritis and cUTIs caused tions for CRE infections resistant to both ertapenem and
by members of the Enterobacterales order [59]. Individual meropenem without additional information regarding
aminoglycosides are equally effective if susceptibility is dem- carbapenemase status. These agents are associated with im-
onstrated. In general, higher percentages of CRE clinical iso- proved clinical outcomes and reduced toxicity compared with
lates are susceptible to amikacin and plazomicin than to other other regimens commonly used to treat CRE infections, which
aminoglycosides [50, 51]. Plazomicin may remain active against are generally polymyxin-based [60–64].
isolates resistant to amikacin. Oral fosfomycin does not achieve Comparative effectiveness studies between the preferred
adequate concentrations in the renal parenchyma and should be agents are limited. An observational study that included 131
avoided if the upper urinary tract is infected [28]. patients with CRE infections found no difference in clinical
Question 3: What are preferred antibiotics for the treat- outcomes between patients treated with ceftazidime-avibactam
ment of infections outside of the urinary tract caused by and patients treated with meropenem-vaborbactam [65].
CRE resistant to ertapenem but susceptible to meropenem Significantly less clinical information is available for imipenem-
when carbapenemase testing results are either not available or cilastatin-relebactam than for the other preferred treatment
negative? options for the treatment of CRE infections. However, in vitro
Recommendation: Extended-infusion meropenem is the pre- activity of this combination against CRE [66–68], clinical expe-
ferred treatment for infections outside of the urinary tract caused rience with imipenem-cilastatin, and the stability of relebactam
by CRE resistant to ertapenem but susceptible to meropenem when as a β-lactamase inhibitor [69] suggest imipenem-cilastatin-
carbapenemase testing results are either not available or negative. relebactam is likely to be effective for CRE infections.
Rationale: Extended-infusion meropenem is recommended Available data suggest that the emergence of ceftazidime-
against infections outside of the urinary tract caused by CRE avibactam resistance is more common than emergence of
that remain susceptible to meropenem since most of these iso- meropenem-vaborbactam resistance following exposure to the
lates do not produce carbapenemases [45]. Meropenem should respective agents [65, 70–74]. As each of these drugs is used
be avoided if carbapenemase testing is positive, even if suscep- more extensively, it is anticipated that additional data on resist-
tibility to meropenem is demonstrated. ance and comparative effectiveness will emerge.

Cefiderocol is an alternative treatment option for CRE infec- treat as if the strain is a KPC producer. Rationale supporting these
tions regardless of the mechanism of resistance to carbapenems. recommendations is provided in Question 4.
Cefiderocol has reliable in vitro activity against CRE, including
If a metallo-β-lactamase (ie, NDM, VIM, or IMP) is identi-
isolates with otherwise highly resistant phenotypes [75–77]. In a
fied, preferred antibiotic options include ceftazidime-avibactam
clinical trial, cefiderocol was compared to best available therapy,
plus aztreonam or cefiderocol monotherapy [86–90]. Clinical
which frequently consisted of colistin-based regimens, for the
outcomes data comparing these 2 treatment strategies are not
treatment of carbapenem-resistant gram-negative infections
available.
in 118 patients; 51% of patients were infected with CRE [57].
If an OXA-48–like enzyme is identified, ceftazidime-
Mortality at 28 days was higher in the cefiderocol arm. These
avibactam is preferred, and cefiderocol is an alternative option.
findings were most striking for the treatment of pneumonia and
Meropenem-vaborbactam and imipenem-cilastatin-relebactam
bloodstream infections. Until more data are available to define
have limited to no activity against CRE-producing OXA-48-like
subpopulations in whom cefiderocol can be used effectively and
enzymes.
safely beyond the urinary tract, the panel recommends that this
In patients with intra-abdominal infections, tigecycline and
agent be reserved for CRE infections for which preferred agents

eravacycline are acceptable monotherapy options [79–81]. The
are unavailable due to intolerance or resistance.
use of tigecycline or eravacycline should generally be limited
If a patient is infected with a CRE strain with unknown
to the treatment of intra-abdominal infections for reasons dis-
carbapenemase status and the patient recently traveled from an
cussed in the rationale for Question 4. High-dose tigecycline
area where metallo-β-lactamases are endemic (eg, Middle East,
may be more effective than standard-dose tigecycline for com-
South Asia, Mediterranean) [78], treatment with ceftazidime-
plicated intra-abdominal infections, as listed in Table 1.
avibactam plus aztreonam or cefiderocol monotherapy is re-
commended. Preferred treatment approaches for infections Question 6: What is the role of polymyxins for the treatment
caused by metallo-β-lactamase producers also provide activity of infections caused by CRE?
against bacteria that produce KPCs or OXA-48–like enzymes. Recommendation: Polymyxin B and colistin should be avoided
In patients with intra-abdominal infections, tigecycline and for the treatment of infections caused by CRE. Colistin can be
eravacycline are acceptable monotherapy options [79–81]; considered as a last resort for uncomplicated CRE cystitis.
high-dose tigecycline may be more effective than standard- Rationale: Observational and randomized, controlled trial
dose tigecycline for complicated intra-abdominal infections, as data indicate increased mortality and excess nephrotoxicity as-
listed in Table 1. Their activity is independent of the presence or sociated with polymyxin-based regimens relative to comparator
type of carbapenemases. The use of tigecycline or eravacycline agents [60–62, 64]. Concerns about the clinical effectiveness of
should generally be limited to the treatment of intra-abdominal polymyxins and accuracy of in vitro polymyxin susceptibility
infections. These agents achieve rapid tissue distribution fol- testing led the Clinical and Laboratory Standards Institute to
lowing administration, resulting in limited concentration in the eliminate a susceptible category for colistin and polymyxin B
urine and poor serum concentrations [82]. [19]. The panel recommends that these agents be avoided for
the treatment of CRE infections, with the exception of colistin
Question 5: What are the preferred antibiotics for the treat-
as a last resort agent against CRE cystitis. Polymyxin B should
ment of infections outside of the urinary tract caused by CRE if
not be used as treatment for CRE cystitis due to its predomi-
carbapenemase production is present?
nantly nonrenal clearance [59].
Recommendation: Ceftazidime-avibactam, meropenem-
vaborbactam, and imipenem-cilastatin-relebactam are the pre- Question 7: What is the role of combination antibiotic
ferred treatment options for KPC-producing infections outside therapy for the treatment of infections caused by CRE?
of the urinary tract. Ceftazidime-avibactam in combination Recommendation: Combination antibiotic therapy (ie, the
with aztreonam or cefiderocol as monotherapy are preferred use of a β-lactam agent in combination with an aminoglycoside,
treatment options for NDM and other metallo-β-lactamase– fluoroquinolone, or polymyxin) is not routinely recommended
producing CRE infections. Ceftazidime-avibactam is the pre- for the treatment of infections caused by CRE.
ferred treatment for OXA-48-like–producing CRE infections. Rationale: Although empiric combination antibiotic therapy to
Rationale: Ceftazidime-avibactam, meropenem-vaborbactam, broaden the likelihood of at least 1 active therapeutic agent for
and imipenem-cilastatin-relebactam provide activity against patients at risk for CRE infections is reasonable, data do not indi-
Enterobacterales that produce KPC enzymes, the most common cate that continued combination therapy, once the β-lactam agent
carbapenemases in the United States [66, 67, 83–85]. If a disease- has demonstrated in vitro activity, offers any additional benefit
causing Enterobacterales is carbapenemase-producing but the [91]. Rather, the continued use of a second agent increases the
specific carbapenemase enzyme is unknown, it is reasonable to likelihood of antibiotic-associated adverse events [91].

Observational data and clinical trials that compare Recommendation: Ceftolozane-tazobactam, ceftazidime-
ceftazidime-avibactam, meropenem-vaborbactam, and avibactam, imipenem-cilastatin-relebactam, cefiderocol, or a
imipenem-cilastatin-relebactam to combination regimens for single dose of an aminoglycoside are the preferred treatment
the treatment of CRE infections have not shown the latter to options for uncomplicated cystitis caused by DTR-P. aeruginosa.
have added value [60–64]. Data from randomized trials that Rationale: Ceftolozane-tazobactam, ceftazidime-
compare these agents as monotherapy and as a component of avibactam, imipenem-cilastatin-relebactam, and
combination therapy (eg, ceftazidime-avibactam vs ceftazidime- cefiderocol are preferred treatment options for uncom-
avibactam and amikacin) are not available. However, based
plicated DTR P. aeruginosa cystitis based on randomized,
on available outcomes data, clinical experience, and known
controlled trials that showed noninferiority of these agents
toxicities associated with aminoglycosides, fluoroquinolones,
to common comparator agents for urinary tract infections
and polymyxins, routine combination therapy for CRE infec-
[53, 55, 56, 92]. Data are insufficient to favor one of the
tions is not recommended when susceptibility to a preferred
β-lactam agent has been demonstrated. agents over the others, and available trials generally do not
include patients infected by pathogens with DTR pheno-

types. Although a clinical trial suggested increased mor-
tality with cefiderocol compared with best available therapy
PSEUDOMONAS AERUGINOSA WITH DIFFICULT-TO-
TREAT RESISTANCE against a variety of infections due to carbapenem-resistant
gram-negative bacteria, these findings do not appear to ex-
The CDC reports that 32 600 cases of multidrug-resistant
P. aeruginosa infection occurred in patients hospitalized in the tend to urinary tract infections [55, 57].
United States in 2017, resulting in 2700 deaths [2]. Multidrug A single dose of an aminoglycoside is also a preferred treat-
resistance is defined as nonsusceptibility to at least 1 antibiotic ment option. Aminoglycosides are nearly exclusively elimin-
in at least 3 classes for which P. aeruginosa susceptibility is gen- ated by the renal route in their active form. A single intravenous
erally expected: penicillins, cephalosporins, fluoroquinolones, dose of an aminoglycoside is generally effective for cystitis, with
aminoglycosides, and carbapenems. In 2018, the concept of minimal toxicity, but robust trial data to formally evaluate their
“difficult-to-treat” resistance (DTR) was proposed [5]. In this activity for cystitis are lacking [23]. Plazomicin is unlikely to
guidance document, DTR is defined as P. aeruginosa that ex- provide any incremental benefit against DTR-P. aeruginosa if
hibits nonsusceptibility to all of the following: piperacillin- resistance to all other aminoglycosides is demonstrated [93].
tazobactam, ceftazidime, cefepime, aztreonam, meropenem, Colistin, but not polymyxin B, is an alternate consideration
imipenem-cilastatin, ciprofloxacin, and levofloxacin. Table 4 for treating DTR-P. aeruginosa cystitis as it converts to its active
outlines preferred and alternative treatment recommendations form in the urinary tract [58]. Clinicians should remain cogni-
for DTR-P. aeruginosa infections. Treatment recommendations
zant of the associated risk of nephrotoxicity. The panel does not
for DTR-P. aeruginosa infections assume in vitro activity of pre-
recommend the use of oral fosfomycin for DTR-P. aeruginosa
ferred and alternative antibiotics has been demonstrated.
cystitis as it is associated with a high likelihood of clinical failure
Question 1: What are preferred antibiotics for the treatment [94, 95]. This is, in part, due to the presence of the fosA gene,
of uncomplicated cystitis caused by DTR-P. aeruginosa? which is intrinsic to P. aeruginosa [24].
Table 4. Recommended Antibiotic Treatment Options for Difficult-to-Treat Pseudomonas aeruginosa, Assuming In Vitro Susceptibility to Agents in Table
Alternative Treatment if First-line Options not Available

Source of Infection Preferred Treatment or Tolerated
Cystitis Ceftolozane-tazobactam, ceftazidime-avibactam, Colistin

imipenem-relebactam, cefiderocol, or a single
dose of an aminoglycoside
Pyelonephritis or complicated Ceftolozane-tazobactam, ceftazidime-avibactam, Once-daily aminoglycosides
urinary tract infectiona imipenem-cilastatin-relebactam, and
cefiderocol
Infections outside of the Ceftolozane-tazobactam, ceftazidime-avibactam, Cefiderocol
urinary tract or imipenem-cilastatin-relebactam Aminoglycoside monotherapy: limited to uncomplicated
bloodstream infections with complete source controlb
a
b
Uncomplicated bloodstream infections include a bloodstream infection that is due to a urinary source or a catheter-related bloodstream infection with removal of the infected vascular
catheter.

Question 2: What are preferred antibiotics for the treat- are similar in their mechanisms of action [106], cross-resistance
ment of pyelonephritis and complicated urinary tract infections between these agents can be observed [107].
(cUTI) caused by DTR-P. aeruginosa? Cefiderocol is an alternative treatment option. Cefiderocol
Recommendation: Ceftolozane-tazobactam, ceftazidime- has reliable in vitro activity against P. aeruginosa, including iso-
avibactam, imipenem-cilastatin-relebactam, and cefiderocol lates with otherwise highly resistant phenotypes [75–77]. In a
are the preferred treatment options for pyelonephritis and clinical trial, cefiderocol was compared to best available therapy,
cUTIs caused by DTR-P. aeruginosa. which frequently consisted of colistin-based regimens, for the
Rationale: A cUTI is defined as a UTI that occurs in as- treatment of carbapenem-resistant gram-negative infections in
sociation with a structural or functional abnormality of the 118 patients; 24% of patients were infected with P. aeruginosa
genitourinary tract, or any UTI in a male patient. Ceftolozane- [57]. Mortality at 28 days was higher in the cefiderocol arm.
tazobactam, ceftazidime-avibactam, imipenem-cilastatin- These findings were most striking for the treatment of pneu-
relebactam, and cefiderocol are preferred treatment options for monia and bloodstream infections. Until more data are avail-
DTR-P. aeruginosa pyelonephritis and cUTIs based on random- able to define subpopulations in whom cefiderocol can be used
ized, controlled trials that showed noninferiority of these agents

effectively and safely beyond the urinary tract, the panel re-
to common comparator agents [53, 55, 56, 92], as discussed in commends that this agent be reserved for DTR-P. aeruginosa
Question 1. In patients in whom the potential for nephrotox- infections in which preferred agents are unavailable due to in-
icity is deemed acceptable, once-daily aminoglycosides is an tolerance or resistance.
alternative option. Plazomicin is unlikely to provide any in- Aminoglycoside monotherapy is an alternative option that
cremental benefit against DTR-P. aeruginosa if resistance to all should be limited to uncomplicated bloodstream infections (ie,
other aminoglycosides is demonstrated [93]. Oral fosfomycin urinary source or other sources for which control is achieved,
should be avoided for DTR-P. aeruginosa pyelonephritis and such as the removal of an infected vascular catheter) when no
cUTIs. This is because of the presence of the fosA gene, which preferred treatment option is available. Plazomicin is unlikely
is intrinsic to P. aeruginosa and confers fosfomycin resistance, to provide any incremental benefit against DTR-P. aeruginosa
and because oral fosfomycin does not achieve adequate con- if resistance to all other aminoglycosides is demonstrated [93].
centrations in the renal parenchyma [24, 28].
Question 4: What is the role of combination antibiotic therapy
Question 3: What are preferred antibiotics for the treat-
for the treatment of infections caused by DTR-P. aeruginosa?
ment of infections outside of the urinary tract caused by
Recommendation: Combination antibiotic therapy is not rou-
DTR-P. aeruginosa?
tinely recommended for infections caused by DTR-P. aeruginosa
Recommendation: Ceftolozane-tazobactam, ceftazidime-
avibactam, and imipenem-cilastatin-relebactam as mono- if in vitro susceptibility to a first-line antibiotic (ie, ceftolozane-
therapy are the preferred treatment options for the tazobactam, ceftazidime-avibactam, or imipenem-cilastatin-
treatment of infections outside of the urinary tract caused by relebactam) has been confirmed.
DTR-P. aeruginosa. Rationale: Although empiric combination antibiotic therapy
Rationale: Ceftolozane-tazobactam, ceftazidime-avibactam, (ie, the addition of an aminoglycoside or polymyxin to a β-lactam
and imipenem-cilastatin-relebactam as monotherapy are pre- agent) to broaden the likelihood of at least 1 active therapeutic
ferred options for the treatment of DTR-P. aeruginosa infections agent for patients at risk for DTR-P. aeruginosa infections is rea-
outside of the urinary tract based on known in vitro activity, ob- sonable, data do not indicate that continued combination therapy,
servational studies, and clinical trial data [53, 64, 83, 85, 96–105]. once the β-lactam agent has demonstrated in vitro activity, offers
The majority of these observational studies and clinical trials did any additional benefit over monotherapy with the β-lactam [91].
not include patients with DTR-P. aeruginosa infections. Clinical Rather, the continued use of a second agent increases the likeli-
outcomes studies that compare the effectiveness of these 3 agents hood of antibiotic-associated adverse events [91].
for DTR-P. aeruginosa infections are not available. Observational data and clinical trials that have compared
The percentage of P. aeruginosa clinical isolates that are sus- ceftolozane-tazobactam and imipenem-cilastatin-relebactam,
ceptible to ceftolozane-tazobactam is generally higher than per- usually given as monotherapy, to combination regimens for
centages susceptible to comparator agents. This is likely because drug-resistant P. aeruginosa infections have not shown the
ceftolozane does not rely on an inhibitor to restore susceptibility to latter to have added value [64, 99]. Randomized trial data that
an otherwise inactive drug (ie, ceftolozane has independent activity compared ceftolozane-tazobactam, ceftazidime-avibactam, or
against DTR-P. aeruginosa). Neither ceftazidime nor imipenem is imipenem-cilastatin-relebactam as monotherapy and as a com-
active against DTR-P. aeruginosa. Avibactam and relebactam ex- ponent of combination therapy are not available (eg, ceftazidime-
pand activity of these agents mainly through inhibition of AmpC, avibactam vs ceftazidime-avibactam and amikacin). Based
but other complex resistance mechanisms are unlikely to be im- on available outcomes data, clinical experience, and known
pacted. Since ceftolozane-tazobactam and ceftazidime-avibactam toxicities associated with aminoglycosides and polymyxins, the

panel agrees that combination therapy is not routinely recom- receives research funding paid to his institution from Melinta and Merck.
mended for DTR-P. aeruginosa infections when susceptibility to R. A. B. receives research funding paid to his institution from VenatoRx,
Merck, Entasis, and Tetraphase. A. J. M. served as an advisor for Rempex;
a preferred β-lactam agent has been demonstrated. serves as a consultant/advisory panel member for Qpex Biopharma,
If no preferred agent demonstrates activity against Acceclerate Diagnostics, VenatoRX, and Antimicrobial Resistance Services.
DTR-P. aeruginosa, an aminoglycoside (if suscepti- D. D. serves as an advisory panel member for Qpex Biopharma and
served as an advisory board member for Shionogi, Entasis, Merck, Roche,
bility is demonstrated) can be considered in combination
Allergan, and Achaogen. C. J. C. served on the advisory board for Merck,
with ceftolozane-tazobactam, ceftazidime-avibactam, or Qpex Biopharma, Astellas, Cidara, and Scynexis; serves as a consultant for
imipenem-cilastatin-relebactam, preferentially selecting the Needham & Associates; and receives research funding paid to his institution
β-lactam-β-lactamase inhibitor agent for which the MIC from Astellas and Merck. All authors have submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest. Conflicts that the editors con-
is closest to its susceptibility breakpoint. For example, if
sider relevant to the content of the manuscript have been disclosed.
ceftolozane-tazobactam and ceftazidime-avibactam MICs
against a DTR-P. aeruginosa isolate are both >128/4 µg/mL References
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learning more about their effectiveness and propensity to de- International Society for Anti-infective Pharmacology (ISAP), Society of Critical
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AMR Treatment Guidance • cid 2021:72 (1 April) • e169

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e170 • cid 2021:72 (1 April) • Tamma et al

Agent Adult Dosage, Assuming Normal Renal and Liver Function

Amikacin Cystitis: 15 mg/kg/dosea IV once

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infections included in this document, if antibiotic susceptibility data EXTENDED-SPECTRUM β-LACTAMASE–PRODUCING

AMR Treatment Guidance • cid 2021:72 (1 April) • e171

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Alternative Treatment if First-line

Cystitis Nitrofurantoin, trimethoprim-sulfamethoxazole Amoxicillin-clavulanate, single-dose

e172 • cid 2021:72 (1 April) • Tamma et al

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Alternative Treatment if First-

Cystitis Ciprofloxacin, levofloxacin, trimethoprim- Ceftazidime-avibactam,

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AMR Treatment Guidance • cid 2021:72 (1 April) • e175

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e176 • cid 2021:72 (1 April) • Tamma et al

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Alternative Treatment if First-line Options not Available

Cystitis Ceftolozane-tazobactam, ceftazidime-avibactam, Colistin

e178 • cid 2021:72 (1 April) • Tamma et al

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AMR Treatment Guidance • cid 2021:72 (1 April) • e179

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e180 • cid 2021:72 (1 April) • Tamma et al

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AMR Treatment Guidance • cid 2021:72 (1 April) • e183

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