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Clinical Infectious Diseases
IDSA GUIDELINES
Infectious Diseases Society of America 2022 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)
Pranita D. Tamma,1 Samuel L. Aitken,2 Robert A. Bonomo,3 Amy J. Mathers,4 David van Duin,5 and Cornelius J. Clancy6
Downloaded from https://academic.oup.com/cid/article/75/2/187/6570801 by guest on 21 December 2022

1
Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; 2Department of Pharmacy, University of Michigan Health, Ann Arbor, Michigan, USA; 3Medical
Service and Center for Antimicrobial Resistance and Epidemiology, Louis Stokes Cleveland 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; 5Department 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. The Infectious Diseases Society of America (IDSA) is committed to providing up-to-date guidance on the
treatment of antimicrobial-resistant infections. The initial guidance document on 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) was published on 17 September 2020. Over the past year, there have been
a number of important publications furthering our understanding of the management of ESBL-E, CRE, and DTR-P. aeruginosa
infections, prompting a rereview of the literature and this updated guidance document.
Methods. A panel of 6 infectious diseases specialists with expertise in managing antimicrobial-resistant infections reviewed,
updated, and expanded previously developed questions and recommendations about the treatment of ESBL-E, CRE, and DTR-
P. aeruginosa infections. Because of differences in the epidemiology of resistance and availability of specific anti-infectives
internationally, this document focuses on the treatment of infections in the United States.
Results. Preferred and alternative treatment recommendations are provided with accompanying rationales, assuming the
causative organism has been identified and antibiotic susceptibility results are known. Approaches to empiric treatment,
duration of therapy, and other management considerations are also discussed briefly. Recommendations apply for both adult
and pediatric populations.
Conclusions. The field of antimicrobial resistance is highly dynamic. Consultation with an infectious diseases specialist is
recommended for the treatment of antimicrobial-resistant infections. This document is current as of 24 October 2021. The most
current versions of IDSA documents, including dates of publication, are available at www.idsociety.org/practice-guideline/amr-
guidance/.
Keywords. ceftolozane-tazobactam; ceftazidime-avibactam; cefiderocol; imipenem-cilastatin-relebactam; meropenem-
vaborbactam.
The rise in antimicrobial resistance (AMR) continues to be a Antibiotic Resistance Threats in the United States Report [1].
global crisis. Collectively, antimicrobial-resistant pathogens The Infectious Diseases Society of America (IDSA) identified
caused more than 2.8 million infections and over 35 000 deaths the development and dissemination of clinical practice
annually from 2012 through 2017, according to the 2019 guidelines and other guidance products for clinicians as a top
Centers for Disease Control and Prevention (CDC) initiative in its 2019 Strategic Plan [2]. IDSA acknowledged
that the ability to address rapidly evolving topics such as
AMR was limited by prolonged timelines needed to generate
Received 07 March 2022; editorial decision 07 March 2022; accepted 04 April 2022; pub- new or updated clinical practice guidelines, which are based
lished online 27 June 2022 on systematic literature reviews and rigorous GRADE
Correspondence: P. D. Tamma, Department of Pediatrics, Johns Hopkins University School of
Medicine, Baltimore, MD, USA (ptamma1@jhmi.edu).
(Grading of Recommendations Assessment, Development,
Clinical Infectious Diseases® 2022;75(2):187–212 and Evaluation) methodology. As an alternative to practice
© The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases guidelines, IDSA endorsed developing more narrowly focused
Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.
com
guidance documents for the treatment of difficult-to-manage
https://doi.org/10.1093/cid/ciac268 infections. Guidance documents are prepared by a small team
AMR Treatment Guidance • CID 2022:75 (15 July) • 187

of experts, who answer questions about treatment based on a In this document, the term complicated urinary tract infec-
comprehensive (but not necessarily systematic) review of the lit- tion (cUTI) refers to UTIs occurring in association with a struc-
erature, clinical experience, and expert opinion. Documents do tural or functional abnormality of the genitourinary tract, or
not include formal grading of evidence, and they are made avail- any UTI in an adolescent or adult male. In general, the panel
able and updated at least annually online. suggests cUTI be treated with similar agents and for similar
In the present document, guidance is provided on the treat- treatment durations as pyelonephritis. For cUTI where the
ment of infections caused by extended-spectrum β-lactamase- source has been controlled (eg, removal of a Foley catheter)
producing Enterobacterales (ESBL-E), carbapenem-resistant and ongoing concerns for urinary stasis or indwelling urinary
Enterobacterales (CRE), and Pseudomonas aeruginosa with hardware are no longer present, it is reasonable to select antibi-
difficult-to-treat resistance (DTR-P. aeruginosa) [3]. These otic agents and treatment durations similar to uncomplicated
pathogens have been designated urgent or serious threats by cystitis.
the CDC [1]. Each pathogen causes a wide range of infections
that are encountered in US hospitals of all sizes and that carry Empiric Therapy

with them significant morbidity and mortality. Empiric treatment decisions should be guided by the most like-
Guidance is presented in the form of answers to a series of ly pathogens, severity of illness of the patient, the likely source
clinical questions for each pathogen. Although brief descrip- of the infection, and any additional patient-specific factors
tions of notable clinical trials, resistance mechanisms, and (eg, severe penicillin allergy, chronic kidney disease). When de-
susceptibility testing methods are included, this document termining empiric treatment for a given patient, clinicians
does not provide a comprehensive review of these topics. Due should also consider: (1) previous organisms identified from
to differences in the molecular epidemiology of resistance the patient and associated antibiotic susceptibility data in
and availability of specific anti-infectives internationally, treat- the last 6 months, (2) antibiotic exposures within the past
ment recommendations are geared toward antimicrobial- 30 days, and (3) local susceptibility patterns for the most likely
resistant infections in the United States. The content of this pathogens. Empiric decisions should be refined based on the
document is current as of 24 October 2021; updates will be pro- identity and susceptibility profile of the pathogen.
vided annually.
Duration of Therapy and Transitioning to Oral Therapy
Recommendations on durations of therapy are not provided,
METHODS
but clinicians are advised that the duration of therapy should
IDSA convened a panel of 6 actively practicing infectious dis- not differ for infections caused by organisms with resistant
eases specialists with clinical and research expertise in the treat- phenotypes compared to infections caused by more susceptible
ment of antimicrobial-resistant bacterial infections. Through a phenotypes. After antibiotic susceptibility results are available,
series of virtual meetings, the panel developed commonly en- it may become apparent that inactive antibiotic therapy was ini-
countered treatment questions and corresponding answers tiated empirically. This may impact the duration of therapy.
for each pathogen group. Answers include a brief discussion For example, cystitis is typically a mild infection [4]. If an an-
of the rationale supporting the recommendations. This guid- tibiotic not active against the causative organism was adminis-
ance document applies to both adult and pediatric populations. tered empirically for cystitis, but clinical improvement
Suggested antibiotic dosing for adults with antimicrobial- nonetheless occurred, the panelists agree that it is generally
resistant infections, assuming normal renal and hepatic func- not necessary to repeat a urine culture, change the antibiotic
tion, is provided in Table 1. regimen, or extend the planned treatment course. However,
for all other infections, if antibiotic susceptibility data indicate
a potentially inactive agent was initiated empirically, a change
GENERAL MANAGEMENT RECOMMENDATIONS
to an active regimen for a full treatment course (dated from
Treatment recommendations in this guidance document the start of active therapy) is recommended. Additionally,
assume that the causative organism has been identified and important host factors related to immune status, ability to at-
that in vitro activity of antibiotics is demonstrated. Assuming tain source control, and general response to therapy should
2 antibiotics are equally effective, safety, cost, convenience, be considered when determining treatment durations for
and local formulary availability are important considerations antimicrobial-resistant infections, as with the treatment of
in selecting a specific agent. The panel recommends that infec- any bacterial infection. Finally, whenever possible, oral step-
tious diseases specialists and physician or pharmacist members down therapy should be considered, particularly if the follow-
of the local antibiotic stewardship program are involved in ing criteria are met: (1) susceptibility to an appropriate oral
the management of patients with infections caused by agent is demonstrated, (2) the patient is hemodynamically sta-
antimicrobial-resistant organisms. ble, (3) reasonable source control measures have occurred, and
188 • CID 2022:75 (15 July) • Tamma et al

Table 1. Suggested Dosing of Antibiotics for the Treatment of Infections Caused by Antimicrobial-Resistant Organisms
Adult Dosage
Agent (Assuming Normal Renal and Liver Functiona) Target Organismsb,c
d
Amikacin Cystitis: 15 mg/kg/dose IV once ESBL-E, AmpC-E, CRE, DTR-P.
All other infections: 20 mg/kg/dosed IV × 1 dose, subsequent doses and aeruginosa
dosing interval based on pharmacokinetic evaluation
Ampicillin-sulbactam 9 g IV q8h over 4 h OR 27 g IV q24h as a continuous infusion CRAB
For mild infections caused by CRAB isolates susceptible to
ampicillin-sulbactam, it is reasonable to administer 3 g IV q4h – particularly if
intolerance or toxicities preclude the use of higher dosages.
Cefepime Cystitis: 1 g IV q8h AmpC-E
All other infections: 2 g IV q8h, infused over 3 h
Cefiderocol 2 g IV q8h, infused over 3 h CRE, DTR-P. aeruginosa, CRAB, S.
maltophilia
Ceftazidime-avibactam 2.5 g IV q8h, infused over 3 h CRE, DTR-P. aeruginosa
Ceftazidime-avibactam and Ceftazidime-avibactam: 2.5 g IV q8h, infused over 3 h Metallo-β-lactamase-producing CRE, S.

aztreonam PLUS maltophilia
Aztreonam: 2 g IV q8h, infused over 3 h, administered at the same time as
ceftazidime-avibactam, if possible
Ceftolozane-tazobactam Cystitis: 1.5 g IV q8h, infused over 1 h DTR-P. aeruginosa
All other infections: 3 g IV q8h, infused over 3 h
Ciprofloxacin ESBL-E or AmpC infections: 400 mg IV q8h-q12h OR 500–750 mg PO q12h ESBL-E, AmpC-E
Colistin Refer to international consensus guidelines on polymyxinse CRE cystitis, DTR-P. aeruginosa cystitis,
CRAB cystitis
Eravacycline 1 mg/kg/dose IV q12h CRE, CRAB
Ertapenem 1 g IV q24h, infused over 30 min ESBL-E, AmpC-E
Fosfomycin Cystitis: 3 g PO × 1 dose ESBL-E. coli cystitis
Gentamicin Cystitis: 5 mg/kg/dosed IV once ESBL-E, AmpC-E, CRE, DTR-P.
All other infections: 7 mg/kg/dosed IV × 1 dose, subsequent doses and aeruginosa
Imipenem-cilastatin Cystitis (standard infusion): 500 mg IV q6h, infused over 30 min ESBL-E, AmpC-E, CRE, CRAB
All other ESBL-E or AmpC-E infections: 500 mg IV q6h, infused over 30 min
All other CRE and CRAB infections: 500 mg IV q6h, infused over 3 h
Imipenem-cilastatin-relebactam 1.25 g IV q6h, infused over 30 min CRE, DTR-P. aeruginosa
Levofloxacin 750 mg IV/PO q24h ESBL-E, AmpC-E, S. maltophilia
Meropenem Cystitis (standard infusion): 1 g IV q8h, infused over 30 min ESBL-E, AmpC-E, CRE, CRAB
All other ESBL-E or AmpC-E infections: 1–2 g IV q8h, infused over 30 min
All other CRE and CRAB infections: 2 g IV q8h, infused over 3 h
Meropenem-vaborbactam 4 g IV q8h, infused over 3 h CRE
Minocycline 200 mg IV/PO q12h CRAB, S. maltophilia
Nitrofurantoin Cystitis: Macrocrystal/monohydrate (Macrobid®) 100 mg PO q12h ESBL-E cystitis, AmpC-E cystitis
Cystitis: Oral suspension: 50 mg PO q6h
Plazomicin Cystitis: 15 mg/kgd IV × 1 dose ESBL-E, AmpC-E, CRE, DTR-P.
All other infections: 15 mg/kgd IV × 1 dose, subsequent doses and dosing aeruginosa
interval based on pharmacokinetic evaluation
Polymyxin B Refer to international consensus guidelines on polymyxinse DTR-P. aeruginosa, CRAB
Tigecycline 200 mg IV × 1 dose, then 100 mg IV q12h CRE, CRAB, S. maltophilia
Tobramycin Cystitis: 5 mg/kg/dosed IV × 1 dose ESBL-E, AmpC-E, CRE, DTR-P.
All other infections: 7 mg/kg/dosed IV × 1 dose; subsequent doses and aeruginosa
Trimethoprim-sulfamethoxazole Cystitis: 160 mg (trimethoprim component) IV/PO q12h ESBL-E, AmpC-E, S. maltophilia
Other infections: 8–12 mg/kg/day (trimethoprim component) IV/PO divided
q8–12h (consider maximum dose of 960 mg trimethoprim component per day)
Abbreviations: AmpC-E, AmpC β-lactamase-producing Enterobacterales; CRAB, carbapenem-resistant Acinetobacter baumannii; CRE, carbapenem-resistant Enterobacterales; DTR-P.
aeruginosa, Pseudomonas aeruginosa with difficult-to-treat resistance; E. coli, Escherichia coli; ESBL-E, extended-spectrum β-lactamase-producing Enterobacterales; IV, intravenous;
MIC, minimum inhibitory concentration; OR, odds ratio; PO, by mouth; q4h, every 4 hours; q6h, every 6 hours; q8h, every 8 hours; q12h, every 12 hours; q24h, every 24 hours;
S. maltophilia, Stenotrophomonas maltophilia
Explanations/References
a
Dosing suggested for several agents in table differs from dosing recommended by the US Food and Drug Administration.
b
Target organisms limited to the following organisms and generally only after susceptibility has been demonstrated: ESBL-E, AmpC-E, CRE, DTR-P. aeruginosa, CRAB, and S. maltophilia.
c
For additional guidance on the treatment of AmpC-E, CRAB, and S. maltophilia, refer to: https://www.idsociety.org/practice-guideline/amr-guidance-2.0/.
d
Use adjusted body weight for patients .120% of ideal body weight for aminoglycoside dosing.
e
Tsuji BT, Pogue JM, Zavascki AP, et al. International Consensus Guidelines for the Optimal Use of the Polymyxins: Endorsed by the American College of Clinical Pharmacy (ACCP), European
Society of Clinical Microbiology and Infectious Diseases (ESCMID), Infectious Diseases Society of America (IDSA), International Society for Anti-infective Pharmacology (ISAP), Society of
Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP). Pharmacotherapy 2019; 39(1): 10–39.

(4) concerns about insufficient intestinal absorption are not these agents preserves their activity for future infections
present [5]. when treatment options may be more restricted. Moreover,
limiting their use reduces the risk of associated toxicities, par-
EXTENDED-SPECTRUM β-LACTAMASE-PRODUCING ticularly with the fluoroquinolones, which have been associated
ENTEROBACTERALES with an increased risk for prolonged QTc intervals, tendinitis
The incidence of ESBL-E identified in bacterial cultures in the and tendon rupture, aortic dissections, seizures, peripheral
United States increased by 53% from 2012 to 2017, in large part neuropathy, and Clostridioides difficile infections, compared
due to increased community-acquired infections [6]. ESBLs are to other antibiotics [22–25].
enzymes that inactivate most penicillins, cephalosporins, and Amoxicillin-clavulanate, single-dose aminoglycosides, and
aztreonam. EBSL-E generally remain susceptible to carbape- oral fosfomycin (for E. coli only) are alternative treatment op-
nems. ESBLs do not inactivate non-β-lactam agents (eg, ciproflox- tions for uncomplicated ESBL-E cystitis. ESBL-E may test sus-
acin, trimethoprim-sulfamethoxazole, gentamicin). However, ceptible to amoxicillin-clavulanate and observational studies
organisms carrying ESBL genes often harbor additional genes demonstrate clinical success with the use of amoxicillin-

or mutations in genes that mediate resistance to a broad range clavulanate for ESBL-E infections [26, 27]. A randomized
of antibiotics. controlled trial (RCT) compared a 3-day regimen of amoxicillin-
Any gram-negative organism has the potential to harbor clavulanate to a 3-day course of ciprofloxacin for 370 women
ESBL genes; however, they are most prevalent in Escherichia with uncomplicated E. coli cystitis [20]. Clinical cure was ob-
coli, Klebsiella pneumoniae, Klebsiella oxytoca, and Proteus served in 58% and 77% of the women randomized to the
mirabilis [7–9]. CTX-M enzymes, particularly CTX-M-15, are amoxicillin-clavulanate and ciprofloxacin arms, respectively.
the most common ESBLs in the United States [8]. ESBLs other The higher failure rates with amoxicillin-clavulanate appear
than CTX-M with unique hydrolyzing abilities are also present, associated with persistent vaginal bacterial colonization,
including variants of narrow-spectrum TEM and SHV which occurred in 45% and 10% of patients in the amoxicillin-
β-lactamases with amino acid substitutions, but have under- clavulanate and ciprofloxacin arms, respectively [20]. The pro-
gone less rigorous clinical investigation than CTX-M enzymes portion of women in the trial infected with ESBL-E strains is
[10–13]. Routine EBSL testing is not performed by most clinical not available, the panel suggests caution with the use of
microbiology laboratories [14, 15]. Rather, non-susceptibility amoxicillin-clavulanate for the treatment of uncomplicated
to ceftriaxone (ie, ceftriaxone minimum inhibitory concentra- ESBL-E cystitis.
tions [MICs] ≥2 mcg/mL) is often used as a proxy for ESBL Aminoglycosides are nearly exclusively eliminated by the re-
production, although this threshold has limitations with specif- nal route in their active form. A single intravenous dose is gen-
icity as organisms not susceptible to ceftriaxone for reasons erally effective for uncomplicated cystitis, with minimal
other than ESBL production may be falsely presumed to be toxicity, but robust clinical trial data are lacking [28].
ESBL-producers [16, 17]. For this guidance document, Oral fosfomycin is an alternative agent exclusively for
ESBL-E will refer to presumed or confirmed ESBL-producing treatment of ESBL-producing E. coli uncomplicated cystitis
E. coli, K. pneumoniae, K. oxytoca, or P. mirabilis. Treatment as the fosA gene, intrinsic to K. pneumoniae and several oth-
recommendations for ESBL-E infections listed below assume er gram-negative organisms, can hydrolyze fosfomycin and
that in vitro activity of preferred and alternative antibiotics may lead to clinical failure [29, 30]. Randomized controlled
has been demonstrated. trial data indicate that oral fosfomycin is associated with
higher clinical failure than nitrofurantoin for uncomplicat-
Question 1: What Are Preferred Antibiotics for the Treatment of ed cystitis [18].
Uncomplicated Cystitis Caused by ESBL-E? The panel does not recommend prescribing doxycycline for
Recommendation: Nitrofurantoin and trimethoprim- the treatment of ESBL-E cystitis. Two clinical outcomes studies,
sulfamethoxazole are preferred treatment options for uncom- published more than 40 years ago, demonstrated that oral tet-
plicated cystitis caused by ESBL-E. racyclines may be effective for the treatment of urinary tract in-
fections (UTIs) [31, 32]. Both of these studies, however,
Rationale primarily focused on P. aeruginosa, an organism not suscepti-
Nitrofurantoin and trimethoprim-sulfamethoxazole have been ble to oral tetracyclines, questioning the impact that antibiotic
shown to be safe and effective options for uncomplicated cysti- therapy had on clinical cure. Doxycycline is primarily eliminat-
tis, including uncomplicated ESBL-E cystitis [4, 18, 19]. ed through the intestinal tract and its urinary excretion is lim-
Although carbapenems and the fluoroquinolones ciprofloxacin ited [33]. Until more robust data demonstrating the clinical
or levofloxacin are effective agents against ESBL-E cystitis [20, effectiveness of oral doxycycline for the treatment of ESBL-E
21], their use for uncomplicated cystitis is discouraged when cystitis are available, the panel recommends against use of dox-
other safe and effective options are available. Limiting use of ycycline for this indication. The roles of piperacillin-

tazobactam, cefepime, and the cephamycins for the treatment Question 3: What Are Preferred Antibiotics for the Treatment of Infections
of uncomplicated cystitis are discussed in Question 4, Outside of the Urinary Tract Caused by ESBL-E?
Question 5, and Question 6. Recommendation: A carbapenem is preferred for the treatment

of infections outside of the urinary tract caused by ESBL-E. After
appropriate clinical response is achieved, transitioning to oral
Question 2: What Are Preferred Antibiotics for the Treatment of
Pyelonephritis and Complicated Urinary Tract Infections Caused by fluoroquinolones or trimethoprim-sulfamethoxazole should
ESBL-E? be considered, if susceptibility is demonstrated.
Recommendation: Ertapenem, meropenem, imipenem-cilastatin,
ciprofloxacin, levofloxacin, or trimethoprim-sulfamethoxazole
are preferred treatment options for pyelonephritis and cUTIs Rationale
caused by ESBL-E. A carbapenem is recommended as first-line treatment of
ESBL-E infections outside of the urinary tract, based primarily
Rationale on data from a large clinical trial [34]. The clinical trial ran-

Carbapenems, ciprofloxacin, levofloxacin, and trimethoprim- domized 391 patients with bloodstream infections due to ceftri-
sulfamethoxazole are all preferred treatment options for axone nonsusceptible E. coli or K. pneumoniae (87% later
patients with ESBL-E pyelonephritis and cUTIs based on the confirmed to have ESBL genes) to piperacillin-tazobactam
ability of these agents to achieve adequate and sustained con- 4.5 g intravenously every 6 hours or meropenem 1 g intrave-
centrations in the urine, RCT results, and clinical experience nously every 8 hours, both as standard infusions. The primary
[34–37]. If a carbapenem is initiated and susceptibility to cipro- outcome of 30-day mortality occurred in 12% and 4% of pa-
floxacin, levofloxacin, or trimethoprim-sulfamethoxazole is tients receiving piperacillin-tazobactam and meropenem, re-
demonstrated, transitioning to these agents is preferred over spectively [34]. Trial data were subsequently reanalyzed only
completing a treatment course with a carbapenem. Limiting including patients with available clinical isolates against which
use of carbapenem exposure will preserve their activity for piperacillin-tazobactam MICs were ≤16 mcg/mL by broth mi-
future antimicrobial-resistant infections. crodilution, the reference standard for antimicrobial suscepti-
In patients in whom the potential for nephrotoxicity is bility testing [45]. Reanalyzing the data from 320 patients,
deemed acceptable, once-daily aminoglycosides for a full treat- 30-day mortality was observed in 11% versus 4% of those in
ment course are an alternative option for the treatment of py- the piperacillin-tazobactam and meropenem arms, respectively.
elonephritis or cUTI [38]. Once-daily plazomicin was Although the absolute risk difference was attenuated and no
noninferior to meropenem in an RCT that included patients longer significant in the reanalysis (ie, the 95% confidence in-
with pyelonephritis and cUTIs caused by the Enterobacterales terval ranged from −1% to 10%) [45], the panel still recom-
[39]. Individual aminoglycosides are equally effective if sus- mends carbapenem therapy as the preferred treatment of
ceptibility is demonstrated. ESBL-producing bloodstream infections due to the overall di-
Nitrofurantoin and oral fosfomycin do not achieve adequate rection of the risk difference. Comparable clinical trial data
concentrations in the renal parenchyma and should be avoided are not available for ESBL-E infections of other body sites.
for pyelonephritis and cUTI [40, 41]. However, fosfomycin is Nevertheless, the panel suggests extrapolating evidence for
an alternative option for the treatment of prostatitis caused ESBL-E bloodstream infections to other common sites of infec-
by ESBL-producing E. coli when preferred options (ie, carbape- tion, namely, pyelonephritis and cUTIs, intra-abdominal infec-
nems, fluoroquinolones, or trimethoprim-sulfamethoxazole) tions, skin and soft tissue infections, and pneumonia.
cannot be tolerated or do not test susceptible [42–44]. The role of oral step-down therapy for ESBL-E infections
Fosfomycin, dosed at 3 g orally daily for 1 week, followed by outside of the urinary tract has not been formally evaluated.
3 g orally every 48 hours for 6–12 weeks, was associated with However, oral step-down therapy has been shown to be a
clinical cure in 82% of patients in an observational study of reasonable treatment consideration for Enterobacterales blood-
44 males with chronic bacterial prostatitis [42]. Fosfomycin stream infections, including those caused by antimicrobial-
should be avoided for prostatitis caused by gram-negative or- resistant isolates, after appropriate clinical milestones are
ganisms other than E. coli (Question 1). achieved [46, 47]. Based on the known bioavailability and sus-
Doxycycline is not recommended for the treatment of tained serum concentrations of oral fluoroquinolones and
ESBL-E pyelonephritis or cUTIs due to its limited urinary ex- trimethoprim-sulfamethoxazole, these agents should be treat-
cretion and limited published comparative effectiveness studies ment considerations for patients with ESBL-E infections if
(Question 1) [33]. The roles of piperacillin-tazobactam, cefe- (1) susceptibility to 1 of these agents is demonstrated, (2) the
pime, and the cephamycins for the treatment of pyelonephritis patient is hemodynamically stable, (3) reasonable source con-
and cUTIs are discussed in Question 4, Question 5, and trol measures have occurred, and (4) concerns about insuffi-
Question 6. cient intestinal absorption are not present [5].

Clinicians should avoid oral step-down to nitrofurantoin, with ESBL-producing E. coli pyelonephritis or cUTI (with confir-
fosfomycin, amoxicillin-clavulanate, doxycycline, or omadacy- mation of the presence of an ESBL gene) randomized to either
cline for ESBL-E bloodstream infections. Nitrofurantoin and piperacillin-tazobactam 4.5 g every 6 hours or ertapenem 1 g ev-
fosfomycin achieve poor serum concentrations [40, 41]. ery 24 hours. Clinical success was similar between both groups at
Amoxicillin-clavulanate and doxycycline achieve unreliable se- 94% for piperacillin-tazobactam and 97% for ertapenem. These
rum concentrations [33, 48]. Omadacycline is a tetracycline de- studies suggest noninferiority between piperacillin-tazobactam
rivative with an oral formulation that may exhibit activity and carbapenems for pyelonephritis or cUTIs.
against ESBL-producing Enterobacterales isolates but has an In the subgroup of 231 patients with ESBL-E bloodstream in-
unfavorable pharmacokinetic-pharmacodynamic profile [49, 50]. fections from a urinary source in the aforementioned RCT com-
Until more clinical data are available investigating omadacy- paring the outcomes of patients with E. coli or K. pneumoniae
cline’s role for the treatment of ESBL-E infections, the panel bloodstream infections treated with piperacillin-tazobactam or
recommends against its use for this indication. meropenem (Question 3), higher mortality was identified in the
piperacillin-tazobactam group (7% vs 3%) [34], although it did

Question 4: Is There a Role for Piperacillin-Tazobactam in the Treatment of not attain statistical significance. Although the panel is unable to
Infections Caused by ESBL-E? state that piperacillin-tazobactam should be avoided for pyelone-
Recommendation: If piperacillin-tazobactam was initiated as phritis or cUTIs, the panel continues to have concerns with the use
empiric therapy for uncomplicated cystitis caused by an organ- of piperacillin-tazobactam for the treatment of ESBL-E infections,
ism later identified as an ESBL-E and clinical improvement even if limited to UTIs, and prefers the use of carbapenem therapy
occurs, no change or extension of antibiotic therapy is neces- (or oral fluoroquinolones or trimethoprim-sulfamethoxazole, if
sary. The panel suggests carbapenems, fluoroquinolones, or susceptible) [Question 2]).
trimethoprim-sulfamethoxazole rather than piperacillin- Observational studies have had conflicting results regarding
tazobactam for the treatment of ESBL-E pyelonephritis and the effectiveness of piperacillin-tazobactam for the treatment of
cUTI, with the understanding that the risk of clinical failure ESBL-E bloodstream infections [26, 53–66]. The effectiveness
with piperacillin-tazobactam may be low. Piperacillin-tazo- of piperacillin-tazobactam for the treatment of invasive
bactam is not recommended for the treatment of infections ESBL-E infections may be diminished by the potential for or-
outside of the urinary tract caused by ESBL-E, even if suscept- ganisms to have increased expression of the ESBL enzyme or
ibility to piperacillin-tazobactam is demonstrated. by the presence of multiple β-lactamases [67]. Additionally,
piperacillin-tazobactam MIC testing may be inaccurate and/
Rationale or poorly reproducible when ESBL enzymes are present, or in
Piperacillin-tazobactam demonstrates in vitro activity against a the presence of other β-lactamase enzymes such as OXA-1,
number of ESBL-E [51]. Observational studies have had conflict- making it unclear if an isolate that tests susceptible to this agent
ing results regarding the effectiveness of piperacillin-tazobactam is indeed susceptible [45, 68–71]. For these reasons, the panel
for the treatment of ESBL-E infections. An RCT of ESBL-E recommends avoiding piperacillin-tazobactam for the treat-
bloodstream infections indicated inferior results with ment of invasive ESBL-E infections.
piperacillin-tazobactam compared to carbapenem therapy
(Question 3) [34]. A second RCT investigating the role of Question 5: Is There a Role for Cefepime in the Treatment of Infections
piperacillin-tazobactam for the treatment of ESBL-E bloodstream Caused by ESBL-E?
infections is ongoing [52]. If piperacillin-tazobactam was initiated Recommendation: Cefepime is not recommended for the treat-
as empiric therapy for uncomplicated cystitis caused by an organ- ment of nonurinary infections caused by ESBL-E, even if sus-
ism later identified as an ESBL-E and clinical improvement oc- ceptibility to the agent is demonstrated. If cefepime was
curs, no change or extension of antibiotic therapy is necessary, initiated as empiric therapy for uncomplicated cystitis caused
as uncomplicated cystitis often resolves on its own. At least 3 ob- by an organism later identified as an ESBL-E and clinical im-
servational studies have compared the efficacy of piperacillin- provement occurs, no change or extension of antibiotic therapy
tazobactam and carbapenems for the treatment of ESBL-E pyelo- is necessary. The panel recommends avoiding cefepime for
nephritis or cUTI [53–55]. The most robust observational study the treatment of pyelonephritis and cUTI. Cefepime is also
included 186 hospitalized patients from 5 hospitals with pyelone- not recommended for the treatment of infections outside of
phritis or cUTI caused by E. coli, K. pneumoniae, K. oxytoca, or the urinary tract caused by ESBL-E, even if susceptibility to
P. mirabilis, with confirmation of the presence of ESBL genes cefepime is demonstrated.
in all isolates. This study identified no difference in the resolution
of clinical symptoms or 30-day mortality between the groups Rationale
[53]. A randomized, open-label clinical trial investigating this No clinical trials comparing the outcomes of patients with
question was also conducted [56]. The trial included 66 patients ESBL-E bloodstream infections treated with cefepime or

carbapenem have been conducted. Cefepime MIC testing may used a variety of cephamycins with differences in dosing, dura-
be inaccurate and/or poorly reproducible if ESBL enzymes are tion, and frequency of administration.
present [72]. If cefepime was initiated as empiric therapy for The panel hesitates to recommend cephamycins for the
uncomplicated cystitis caused by an organism later identified treatment of ESBL-E infections, including ESBL-E uncompli-
as an ESBL-E and clinical improvement occurs, no change or cated cystitis. Many of the cephamycins investigated in obser-
extension of antibiotic therapy is necessary, as uncomplicated vational studies are not available in the United States. Only
cystitis often resolves on its own. Limited data are available 31 patients received cefoxitin (and none received cefotetan)
evaluating the role of cefepime versus carbapenems for in published studies [83, 87]. The panel believes more clinical
ESBL-E pyelonephritis and cUTIs [56, 73]. A clinical trial data with use of these agents for the treatment of ESBL-E infec-
evaluating the treatment of molecularly confirmed ESBL-E tions is necessary before recommending their use—including
pyelonephritis and cUTI was terminated early because of a optimal dosing and frequency of administration—especially
high clinical failure signal with cefepime (2 g intravenously in light of the 2 observational studies suggesting poorer clinical
every 12 hours), despite all isolates having cefepime MICs of outcomes with cephamycin use. At least 1 study suggested fa-

1–2 mcg/mL [56]. It is unknown if results would have been vorable outcomes with high-dose, continuous infusion cefoxi-
more favorable with 8-hour cefepime dosing. Until larger, tin (ie, 6 g per day infused continuously) [87], which is
more robust comparative effectiveness studies are available to challenging to administer. As both cephamycin and cefoxitin
inform the role of cefepime, the panel suggests avoiding cefe- are only available intravenously and have relatively short half-
pime for the treatment of ESBL-E pyelonephritis or cUTI. lives, there does not appear to be a feasibility advantage with
Observational studies and a subgroup analysis of 23 patients use of these agents over preferred agents for the treatment of
in an RCT that compared cefepime and carbapenems for the ESBL-E infections.
treatment of invasive ESBL-E infections demonstrated either
no difference in outcomes or poorer outcomes with cefepime
CARBAPENEM-RESISTANT ENTEROBACTERALES
[74–77]. For these reasons, the panel recommends avoiding ce-
fepime for the treatment of invasive ESBL-E infections. CRE account for more than 13 000 nosocomial infections and
contribute to greater than 1000 deaths in the United States annu-
Question 6: Is There a Role for the Cephamycins in the Treatment of ally [1]. The CDC defines CRE as members of the
Infections Caused by ESBL-E? Enterobacterales order resistant to at least 1 carbapenem antibi-
Recommendation: Cephamycins are not recommended for the otic or producing a carbapenemase enzyme [88]. Regarding bac-
treatment of ESBL-E infections until more clinical outcomes teria that are intrinsically not susceptible to imipenem (eg,
data using cefoxitin or cefotetan are available and optimal dos- Proteus spp., Morganella spp., Providencia spp.), resistance to
ing has been defined. at least 1 carbapenem other than imipenem is required [88].
CRE comprise a heterogenous group of pathogens with multiple
Rationale potential mechanisms of resistance, broadly divided into those
The cephamycins are cephalosporins that are generally able to that are carbapenemase-producing and those that are not
retain in vitro activity against ESBL enzymes [78, 79]. The carbapenemase-producing. CRE that are not carbapenemase-
cephamycins available in the United States are cefoxitin and ce- producing may be the result of amplification of non-
fotetan, which are both intravenous agents. At least 8 retrospec- carbapenemase β-lactamase genes with concurrent outer mem-
tive observational studies have compared the clinical outcomes brane porin disruption [89]. Carbapenemase-producing isolates
of patients with ESBL-E infections—generally UTIs or blood- account for approximately 35–59% of CRE cases in the United
stream infections with urinary sources—treated with cephamy- States [90, 91].
cins versus carbapenems [80–87]. Six of the 8 investigations The most common carbapenemases in the United States are
found no difference in clinical outcomes [80, 82–84, 86, 87], K. pneumoniae carbapenemases (KPCs), which can be produced
whereas 2 studies demonstrated poorer outcomes with cepha- by any Enterobacterales. Other notable carbapenemases
mycins [81]. One of the 2 studies included 57 patients with that have been identified in the United States include New
K. pneumoniae bloodstream infections, 14-day mortality was Delhi metallo-β-lactamases (NDMs), Verona integron-encoded
55% and 39% in the cephamycin and carbapenem arms, respec- metallo-β-lactamases (VIMs), imipenem-hydrolyzing metallo-
tively [81]. The second study was the largest study published to β-lactamases (IMPs), and oxacillinases (eg, OXA-48-like)
date, including 380 patients with E. coli and K. pneumoniae [92, 93]. Knowledge of whether a CRE clinical isolate is
bloodstream infections, and 30-day mortality was 29% versus carbapenemase-producing and, if it is, the specific carbapene-
13% in the cephamycin and carbapenem arms, respectively mase produced is important in guiding treatment decisions.
[85]. Importantly, all 8 studies were generally small, included Phenotypic tests such as the modified carbapenem inactivation
diverse sources of infection, had notable selection bias, and method and the Carba NP test can differentiate carbapenemase-

and non-carbapenemase-producing CRE [94]. Molecular testing Individual aminoglycosides are equally effective if susceptibil-
can identify specific carbapenemase families (eg, differentiating ity is demonstrated. In general, higher percentages of CRE clin-
a KPC from an OXA-48-like carbapenemase). Carbapenemase ical isolates are susceptible to amikacin and plazomicin than to
phenotypic and/or genotypic testing are performed by a minor- other aminoglycosides [97, 98]. Plazomicin may remain active
ity of clinical microbiology laboratories, but the panel strongly against isolates resistant to amikacin [99].
encourages all clinical microbiology laboratories to pursue car- If none of the preferred agents is active, ceftazidime-avibactam,
bapenemase testing to inform optimal treatment decisions. meropenem-vaborbactam, imipenem-cilastatin-relebactam, and
Treatment recommendations for CRE infections listed below cefiderocol are alternative options for uncomplicated CRE cystitis.
assume that in vitro activity of preferred and alternative antibi- Data are insufficient to favor 1 agent over the others, but all of
otics has been demonstrated. these agents are reasonable treatment options based on published
comparative effectiveness studies [100–105].
Question 1: What Are Preferred Antibiotics for the Treatment of Fosfomycin use should be limited to uncomplicated CRE
Uncomplicated Cystitis Caused by CRE? cystitis caused by E. coli as the fosA gene (intrinsic to certain

Recommendation: Ciprofloxacin, levofloxacin, trimethoprim- gram-negative organisms such as Klebsiella spp., Enterobacter
sulfamethoxazole, nitrofurantoin, or a single-dose of an amino- spp., and Serratia marcescens) can hydrolyze fosfomycin
glycoside are preferred treatment options for uncomplicated and may lead to clinical failure [29, 30]. Randomized con-
cystitis caused by CRE. Standard infusion meropenem is a trolled trial data indicate that oral fosfomycin is associated
preferred treatment option for cystitis caused by CRE resistant with higher clinical failure than nitrofurantoin for uncompli-
to ertapenem (ie, ertapenem MICs ≥2 mcg/mL) but susceptible cated cystitis [18].
to meropenem (ie, meropenem MICs ≤1 mcg/mL), when carba- Colistin is an alternative agent for treating uncomplicated
penemase testing results are either not available or negative. If CRE cystitis only if none of the above agents is an option.
none of the preferred agents are active, ceftazidime-avibactam, Colistin converts to its active form in the urinary tract; clini-
meropenem-vaborbactam, imipenem-cilastatin-relebactam, or cians should remain cognizant of the associated risk of nephro-
cefiderocol are alternative options for uncomplicated CRE toxicity [106]. Polymyxin B should not be used as treatment for
cystitis. uncomplicated CRE cystitis, due to its predominantly nonrenal
clearance [107].
Rationale
Clinical trial data evaluating the efficacy of most preferred Question 2: What Are Preferred Antibiotics for the Treatment of
agents for uncomplicated CRE cystitis are not available. Pyelonephritis and Complicated Urinary Tract Infections Caused by CRE?
However, as ciprofloxacin, levofloxacin, trimethoprim- Recommendation: Ciprofloxacin, levofloxacin, and trimethoprim-
sulfamethoxazole, nitrofurantoin, or a single dose of an ami- sulfamethoxazole are preferred treatment options for pyelo-
noglycoside all achieve high concentrations in urine, they nephritis and cUTI caused by CRE if susceptibility is
are expected to be effective for uncomplicated CRE cystitis, demonstrated. Extended-infusion meropenem is a preferred
when active [4, 18–21]. Meropenem is a preferred agent treatment option for pyelonephritis and cUTIs caused by CRE
against uncomplicated CRE cystitis for isolates that remain resistant to ertapenem (ie, ertapenem MICs ≥2 mcg/mL) but
susceptible to meropenem because most of these isolates do susceptible to meropenem (ie, meropenem MICs ≤1 mcg/mL),
not produce carbapenemases [95]. Meropenem should be when carbapenemase testing results are either not available or
avoided if carbapenemase testing is positive, even if suscepti- negative. Ceftazidime-avibactam, meropenem-vaborbactam,
bility to meropenem is demonstrated. There is uncertainty imipenem-cilastatin-relebactam, and cefiderocol are also pre-
about the accuracy of meropenem MICs in these scenarios, ferred treatment options for pyelonephritis and cUTIs caused
and use of meropenem may lead to treatment failure [96]. by CRE resistant to both ertapenem and meropenem.
Some agents listed as alternative options for ESBL-E cystitis
(eg, fluoroquinolones) are recommended as preferred agents Rationale
for CRE cystitis. These agents are not preferred agents for Although the minority of CRE are expected to retain susceptibility
the treatment of uncomplicated ESBL-E cystitis in order to to ciprofloxacin, levofloxacin, or trimethoprim-sulfamethoxazole,
preserve their activity for more invasive infections. They are, these agents are all preferred agents to treat CRE pyelonephri-
however, preferred agents against uncomplicated CRE cystitis tis or cUTI after susceptibility is demonstrated [35–37].
because there are generally fewer treatment options available Extended-infusion meropenem is a preferred agent against
for these infections. pyelonephritis and cUTI by CRE that remain susceptible to
Aminoglycosides are almost exclusively eliminated by the re- meropenem, because most of these isolates do not produce car-
nal route in their active form. A single intravenous dose is gen- bapenemases (Table 1) [90]. Meropenem should be avoided if
erally effective for cystitis, with minimal toxicity [28]. carbapenemase testing is positive, even if susceptibility to

meropenem is demonstrated. There is uncertainty about the ac- CDC characterized over 42 000 CRE isolates collected from
curacy of meropenem MICs in these scenarios, and use of mer- all regions of the United States between 2017 and 2019 and
openem may lead to treatment failure [96]. found that only approximately 10% of CRE isolates containing
Ceftazidime-avibactam, meropenem-vaborbactam, imipenem- a carbapenemase gene retained susceptibility to meropenem
cilastatin-relebactam, and cefiderocol are preferred treatment [108]. The panel recommends that meropenem be avoided if
options for pyelonephritis and cUTIs caused by CRE resistant carbapenemase testing is positive, even if susceptibility to
to both ertapenem and meropenem based on RCTs showing meropenem is demonstrated. Although studies indicating
non-inferiority of these agents to common comparator agents the optimal treatment approach when phenotypic-genotypic
for UTIs [100–105]. Data are insufficient to favor 1 agent over discordance exists are not available, the panel prefers to err
the others. on the side of caution.
In patients in whom the potential for nephrotoxicity is Ceftazidime-avibactam is recommended as an alternative
deemed acceptable, once-daily aminoglycosides for a full treat- agent for the treatment of ertapenem-resistant, meropenem-
ment course are an alternative option [38]. Once-daily plazo- susceptible CRE infections outside of the urinary tract

micin was noninferior to meropenem in an RCT that (Question 4). The panel prefers to reserve ceftazidime-avibactam
included patients with pyelonephritis and cUTIs caused by for the treatment of infections caused by CRE resistant to all
the Enterobacterales [39]. Individual aminoglycosides are carbapenems to preserve its activity. The panel recommends
equally effective if susceptibility is demonstrated. In general, against the use of meropenem-vaborbactam or imipenem-
higher percentages of CRE clinical isolates are susceptible to cilastatin-relebactam to treat ertapenem-resistant, meropenem-
amikacin and plazomicin than to other aminoglycosides [97, susceptible infections caused by CRE since these agents are
98]. Plazomicin may remain active against isolates resistant unlikely to offer any significant advantage beyond that of
to amikacin [97, 98]. Nitrofurantoin and oral fosfomycin do extended-infusion meropenem (ie, the addition of vaborbac-
not achieve adequate concentrations in the renal parenchyma tam or relebactam is unlikely to provide any incremental ben-
and should be avoided for pyelonephritis and cUTI [40, 41]. efit compared with a carbapenem alone).
Question 3: What Are Preferred Antibiotics for the Treatment of Infections Question 4: What Are the Preferred Antibiotics for the Treatment of
Outside of the Urinary Tract Caused by CRE Resistant to Ertapenem but Infections Outside of the Urinary Tract Caused by CRE Resistant to Both
Susceptible to Meropenem, When Carbapenemase Testing Results Are Ertapenem and Meropenem, When Carbapenemase Testing Results Are
Either Not Available or Negative? Either Not Available or Negative?
Recommendation: Extended-infusion meropenem is the pre- Recommendation: Ceftazidime-avibactam, meropenem-
ferred treatment for infections outside of the urinary tract vaborbactam, and imipenem-cilastatin-relebactam are the pre-
caused by CRE resistant to ertapenem (ie, ertapenem MICs ferred treatment options for infections outside of the urinary
≥2 mcg/mL) but susceptible to meropenem (ie, meropenem tract caused by CRE resistant to both ertapenem (ie, ertapenem
MICs ≤1 mcg/mL), when carbapenemase testing results are ei- MICs ≥2 mcg/mL) and meropenem (ie, meropenem MICs
ther not available or negative. ≥4 mcg/mL), when carbapenemase testing results are either
not available or negative. For patients with CRE infections
Rationale who within the previous 12 months have received medical
The panel believes that all clinical microbiology laboratories in care in countries with a relatively high prevalence of
the United States should develop approaches to detect carbape- metallo-β-lactamase-producing organisms or who have pre-
nemase production in CRE clinical isolates, including identify- viously had a clinical or surveillance culture where a
ing the specific carbapenemase present (eg, KPC, NDM, metallo-β-lactamase-producing isolate was identified, pre-
OXA-48-like). The panel understands that most US clinical mi- ferred treatment options include the combination of
crobiology laboratories do not currently perform this testing ceftazidime-avibactam plus aztreonam, or cefiderocol as
and/or that there may be delays in identifying the presence of monotherapy, if carbapenemase testing results are not
carbapenemases and in determining susceptibility to novel available.
β-lactam agents (ie, ceftazidime-avibactam, meropenem-
vaborbactam, imipenem-cilastatin-relebactam, cefiderocol). Rationale
Therefore, an understanding of which novel agents may be ac- CDC data from 2017 to 2019 indicate that approximately 35%
tive against CRE isolates is important. of CRE clinical or surveillance isolates in the United States car-
Extended-infusion meropenem is recommended against in- ry 1 of the main 5 carbapenemase genes [90]. Of these 35% of
fections outside of the urinary tract caused by CRE that remain isolates, the specific prevalence by carbapenemase gene is as fol-
susceptible to meropenem since most of these isolates do not lows: blaKPC (86%), blaNDM (9%), blaVIM (,1%), blaIMP (1%),
produce carbapenemases [90]. Recommended dosing for or blaOXA-48-like (4%) [90]. A separate cohort of 1040 clinical
extended-infusion meropenem is provided in Table 1. The and surveillance CRE isolates from across the United States

demonstrated that 59% of isolates were carbapenemase pro- preferred treatment options include the combination of
ducing, with the distribution of carbapenemase genes relatively ceftazidime-avibactam plus aztreonam, or cefiderocol as
similar: blaKPC (92%), blaNDM (3%), blaVIM (,1%), blaIMP monotherapy (Question 5). However, if carbapenemase
(,1%), and blaOXA-48-like (3%) [91]. testing is available and is negative, monotherapy with
Ceftazidime-avibactam has activity against most KPC- and ceftazidime-avibactam, meropenem-vaborbactam, or imipenem-
OXA-48-like-producing CRE [109, 110]. Meropenem- cilastatin-relebactam are preferred treatment options.
vaborbactam and imipenem-cilastatin-relebactam are active Tigecycline or eravacycline (as monotherapy) are alternative
against most Enterobacterales that produce KPC enzymes but options for the treatment of CRE infections not involving the
not those that produce OXA-48-like carbapenemases [111–119]. bloodstream or urinary tract (Question 7). Their activity is in-
Neither ceftazidime-avibactam, meropenem-vaborbactam, dependent of the presence or type of carbapenemase.
nor imipenem-cilastatin-relebactam have activity against
metallo-β-lactamase (eg, NDM)-producing Enterobacterales. Question 5: What Are the Preferred Antibiotics for the Treatment of
As described above, the vast majority of CRE clinical isolates ei- Infections Outside of the Urinary Tract Caused by CRE if Carbapenemase
Production is Present?

ther do not produce carbapenemases or, if they do, produce
KPCs. Therefore, all 3 of these agents (ie, ceftazidime-avibactam, Recommendation: Meropenem-vaborbactam, ceftazidime-
meropenem-vaborbactam, imipenem-cilastatin-relebactam) are avibactam, and imipenem-cilastatin-relebactam are preferred
preferred treatment options for CRE clinical isolates outside of treatment options for KPC-producing infections outside of the
the urinary tract caused by CRE resistant to both ertapenem urinary tract. Ceftazidime-avibactam in combination with az-
and meropenem when carbapenemase testing results are either treonam, or cefiderocol as monotherapy, are preferred treatment
not available or negative. There are not data indicating differenc- options for NDM and other metallo-β-lactamase-producing in-
es in the effectiveness of these agents when susceptibility has fections. Ceftazidime-avibactam is the preferred treatment op-
been demonstrated (Question 5). tion for OXA-48-like-producing infections.
Previously, it was considered standard practice to administer
extended-infusion meropenem in combination with a second Rationale
agent, frequently polymyxins or aminoglycosides, for the treat- Preferred agents for CRE infections differ based on the identi-
ment of infections caused by CRE isolates with meropenem fication of specific carbapenemases [135]. Tigecycline or erava-
MICs as high as 8–16 mcg/mL [120]. Data suggested that cycline, but not omadacycline, are alternative options for the
extended-infusion meropenem remained active against infec- treatment of CRE infections (Question 7). Their activity is in-
tions caused by organisms with carbapenem MICs in this range dependent of the presence or type of carbapenemase produced.
[121–123]. However, subsequent observational and RCT data
indicate increased mortality and excess nephrotoxicity associ- KPC Producers. For KPC-producing organisms, preferred agents
ated with polymyxin or aminoglycoside-based regimens rela- include meropenem-vaborbactam, ceftazidime-avibactam, or
tive to newer β-lactam-β-lactamase inhibitor agents for the imipenem-cilastatin-relebactam [109, 111–116, 136]. These agents
treatment of CRE infections [124–132]. Therefore, the panel are associated with improved clinical outcomes and reduced tox-
does not recommend the use of extended-infusion carbape- icity compared to other regimens commonly used to treat
nems with or without the addition of a second agent for the KPC-producing infections, which are often polymyxin-based
treatment of CRE when non-susceptibility to meropenem has [124–132, 136].
been demonstrated. Comparative effectiveness studies between the preferred
Cefiderocol is also likely to be active against most CRE clin- agents are limited and no clinical trials exist comparing the novel
ical isolates as it exhibits activity against Enterobacterales pro- agents. An observational study compared the clinical outcomes
ducing any of the 5 major carbapenemase enzymes [133]. of patients who received either meropenem-vaborbactam or
However, the panel recommends cefiderocol as an alternative ceftazidime-avibactam for at least 72 hours for the treatment
agent for infections caused by CRE other than metallo-β- of CRE infections [137]. Carbapenemase status was largely
lactamase-producing Enterobacterales (eg, NDM, VIM, IMP) unavailable. Clinical cure and 30-day mortality between the
(Question 5). Patients with CRE infections who have received 26 patients who received meropenem-vaborbactam and 105
medical care in countries with a relatively high prevalence of patients who received ceftazidime-avibactam were similar
metallo-β-lactamase-producing CRE within the previous at 69% and 62% and 12% and 19%, respectively. Of patients
12 months [134] or who have previously had a clinical or surveil- who experienced recurrent CRE infections, 0 of 3 patients re-
lance culture where metallo-β-lactamase-producing organisms ceiving meropenem-vaborbactam, and 3 of 15 patients re-
were identified have a high likelihood of being infected ceiving ceftazidime-avibactam had subsequent CRE isolates
with metallo-β-lactamase-producing Enterobacterales. For that developed resistance to initial therapy. This study had a
such patients (if carbapenemase results are not available), number of important limitations: likely selection bias due to its

observational nature, relatively small numbers of patients, heter- with suboptimal outcomes. However, the panel recommends ce-
ogenous sites of CRE infection, more than half of patients had fiderocol as an alternative agent for treating KPC-producing
polymicrobial infections, and more than half of patients received pathogens as it prefers its activity be reserved for the treatment
additional antibiotic therapy. These limitations notwithstanding, of metallo-β-lactamase-producing Enterobacterales (eg, NDM,
this study suggests that meropenem-vaborbactam and VIM, IMP producers) or for select glucose non-fermenting
ceftazidime-avibactam are associated with similar clinical gram-negative organisms [143].
outcomes, although the emergence of resistance may be
more common with ceftazidime-avibactam (Question 6). NDM Producers. If Enterobacterales isolates produce NDMs
Therefore, the panel expresses a slight preference for the use (or any other metallo-β-lactamase), preferred antibiotic op-
of meropenem-vaborbactam over ceftazidime-avibactam for tions include ceftazidime-avibactam plus aztreonam, or cefider-
the treatment of KPC-producing organisms, but both are pre- ocol monotherapy [105, 144–149]. Ceftazidime-avibactam
ferred options for this indication. (monotherapy), meropenem-vaborbactam, and imipenem-
Limited clinical data are available for imipenem-cilastatin- cilastatin-relebactam are not effective against metallo-β-lacta-

relebactam compared with the other novel β-lactam-β-lactamase mase producing infections.
inhibitor agents. A clinical trial randomized patients with in- NDMs hydrolyze penicillins, cephalosporins, and carbape-
fections caused by gram-negative organisms not susceptible nems but not aztreonam. Although aztreonam is active against
to imipenem receiving imipenem-cilastatin-relebactam ver- NDMs, it can be hydrolyzed by ESBLs, AmpC β-lactamases, or
sus imipenem-cilastatin and colistin [127]. Of patients with OXA-48-like carbapenemases, which are frequently co-produced
Enterobacterales infections, 40% (2 of 5 patients) and 100% by NDM-producing isolates. Avibactam generally remains effec-
(2 of 2 patients) experienced a favorable clinical response with tive against these latter β-lactamase enzymes. An observational
imipenem-cilastatin-relebactam and imipenem-cilastatin in com- study of 102 adults with bloodstream infections caused by
bination with colistin, respectively [127]. It is difficult to draw metallo-β-lactamase-producing Enterobacterales compared the
meaningful conclusions from these data given the small numbers. outcomes of 52 patients receiving ceftazidime-avibactam in
However, in vitro activity of imipenem-cilastatin-relebactam combination with aztreonam versus 50 patients receiving a
against CRE [118, 138–141], clinical experience with imipenem- combination of other agents, primarily polymyxin or
cilastatin, and the stability of relebactam as a β-lactamase in- tigecycline-based therapy [149]. Thirty-day mortality was
hibitor [142] suggest imipenem-cilastatin-relebactam is likely to 19% for the ceftazidime-avibactam/aztreonam group and
be effective for CRE infections if it tests susceptible. Studies com- 44% for the alternate arm, highlighting the potential clinical
paring the clinical outcomes of imipenem-cilastatin-relebactam benefit with the former. When the combination of
and ceftazidime-avibactam or meropenem-vaborbactam for ceftazidime-avibactam and aztreonam are administered to
CRE infections are not available. Although ceftazidime-avibactam, treat metallo-β-lactamase producing infections, it is recom-
meropenem-vaborbactam, and imipenem-cilastatin-relebactam mended that they be administered simultaneously rather
are all recommended as preferred agents for the treatment of than sequentially [150].
KPC-producing infections, the panel slightly favors meropenem- Another preferred option for the treatment of NDM and
vaborbactam, followed by ceftazidime-avibactam, and then other metallo-β-lactamase-producing Enterobacterales is cefi-
imipenem-cilastatin-relebactam, based on available data. derocol. Surveillance data indicate that NDM-producing
Cefiderocol is an alternative treatment option for Enterobacterales isolates have a higher cefiderocol MIC90
KPC-producing Enterobacterales [133]. A clinical trial found than isolates that produce serine β-lactamases, although this
that clinical cure occurred in 66% (19 of 29) and 45% (5 of 11) is not always associated with frank cefiderocol resistance
of CRE infected patients treated with cefiderocol versus alterna- [133, 151]. Among 151 international CRE isolates, cefiderocol
tive agents (mostly polymyxin-based regimens), respectively was active against 98% of all isolates [133]. On closer inspection,
[105]. All-cause mortality was 23% (9 of 40) versus 21% (4 of cefiderocol was active against 100% of 75 KPC-producing
19) in patients with carbapenem-resistant K. pneumoniae or Enterobacterales isolates, 100% of 32 OXA-48-like isolates, but
carbapenem-resistant E. coli, treated with cefiderocol versus al- only 58% of the 12 NDM-producing Enterobacterales isolates,
ternative agents, respectively. When patients with concomitant using cefiderocol MICs of ≤4 mcg/mL as indicative of suscept-
Acinetobacter infection were excluded, all-cause mortality was ibility [133]. Similar data on the percent of NDM-producing
19% (6 of 31) versus 25% (4 of 16) in patients with K. pneumo- isolates susceptible to the combination of ceftazidime-avibactam
niae or E. coli treated with cefiderocol versus alternative therapy, and aztreonam are not available, in part because there is no
respectively. Although clinical investigations comparing the ef- Clinical and Laboratory Standards Institute (CLSI)-standardized
fectiveness of cefiderocol versus newer β-lactam-β-lactamase in- approach to identifying in vitro activity of this antibiotic com-
hibitors for KPC-producing Enterobacterales infections are not bination against bacterial isolates [15]. A clinical trial includ-
available, available data do not suggest cefiderocol is associated ing patients with metallo-β-lactamase producing infections

(not limited to the Enterobacterales) found that clinical cure emergence of resistance to imipenem-cilastatin-relebactam.
occurred in 75% (12 of 16) and 29% (2 of 7) of patients receiv- Whether this is indicative of the successful properties of this
ing cefiderocol versus alternate therapy (primarily polymyxin- combination or the result of limited use is not clear. Similarly,
based therapy), respectively [105]. Clinical outcomes data estimates of the frequency of the emergence of resistance to ce-
comparing ceftazidime-avibactam in combination with az- fiderocol since its clinical introduction are not yet available.
treonam versus cefiderocol are not available. The panel recom- The panel recommends always repeating antibiotic suscept-
mends both treatment options as preferred options for ibility testing for the newer β-lactams when a patient previously
metallo-β-lactamase-producing Enterobacterales. infected with a CRE presents with a sepsis-like picture sugges-
tive of a new or relapsed infection. Furthermore, if a patient was
OXA-48-like Producers. If an OXA-48-like enzyme is identified, recently treated with ceftazidime-avibactam and presents with
ceftazidime-avibactam is preferred [109, 110, 152], and cefider- a sepsis-like condition, the panel suggests considering use of a
ocol is an alternative option. Meropenem-vaborbactam and different novel β-lactam agent at least until culture and suscept-
imipenem-cilastatin-relebactam have limited to no activity ibility data are available. For example, if a patient with a

against CRE producing OXA-48-like enzymes [111–119]. KPC-producing bloodstream infection received a treatment
Although OXA-48-like producing isolates are generally expect- course of ceftazidime-avibactam 1 month earlier and presents
ed to test susceptible to cefiderocol, clinical data on cefiderocol to medical care with symptoms suggestive of infection, consid-
treatment of infections by these organisms are limited. er administering an agent such as meropenem-vaborbactam
until organism and susceptibility data are available.
Question 6: What Is the Likelihood of the Emergence of Resistance of CRE
Isolates to the Newer β-Lactam Agents When Used to Treat CRE Question 7: What Is the Role of Tetracycline Derivatives for the Treatment
Infections? of Infections Caused by CRE?
Recommendation: The emergence of resistance is a concern with Recommendation: Although β-lactam agents remain preferred
all of the novel β-lactams used to treat CRE infections, but the treatment options for CRE infections, tigecycline and eravacy-
frequency appears to be the highest for ceftazidime-avibactam. cline are alternative options when β-lactam agents are either
not active or unable to be tolerated. The tetracycline derivatives
Rationale are not recommended as monotherapy for the treatment of
As with most antibiotic agents, treatment with any of the newer CRE urinary tract infections or bloodstream infections.
β-lactam agents active against CRE (ie, ceftazidime-avibactam,
meropenem-vaborbactam, imipenem-cilastatin-relebactam, or Rationale
cefiderocol) increases the likelihood that subsequent isolates Tetracycline derivatives function independent of the presence or
causing infection will no longer be effectively treated with these type of carbapenemase. More specifically, both carbapenemase-
agents. The emergence of resistance to ceftazidime-avibactam producing (eg, KPC, NDM, OXA-48-like carbapenemases)
most commonly occurs because of mutations in the blaKPC and non-carbapenemase-producing CRE may test suscepti-
gene translating to amino acid changes in the KPC carbape- ble to these agents [112, 190]. The tetracycline-derivative
nemase [153–169]. Changes in permeability and efflux agents generally achieve rapid tissue distribution following
are the primary drivers of the emergence of resistance to administration, resulting in limited urine and serum concen-
meropenem-vaborbactam [113, 162, 166, 170–176] and trations [191]. Therefore, the panel recommends avoiding
imipenem-cilastatin-relebactam [177, 178]. A number of di- their use for urinary and bloodstream infections.
verse mechanisms of resistance to cefiderocol have been de- Tigecycline or eravacycline can be considered as alternative
scribed including mutations in the TonB-dependent iron options for intra-abdominal infections, skin and soft tissue
transport system [179–182], amino acid changes in AmpC infections, osteomyelitis, and respiratory infections when op-
β-lactamases [183, 184], and increased NDM expression timal dosing is used (Table 1).
[185]. The reader is referred to review articles on this topic Tigecycline has more published experience available for the
for a more complete understanding of the mechanisms of resis- treatment of CRE infections than eravacycline [192–195]. A
tance to the novel β-lactams [143, 186, 187]. meta-analysis of 15 randomized trials suggested that tigecycline
Estimates of the emergence of resistance after clinical exposure monotherapy is associated with higher mortality than alterna-
to ceftazidime-avibactam and meropenem-vaborbactam are ap- tive regimens used for the treatment of pneumonia, not exclu-
proximately 20% [128, 132, 157, 188] and 3% [137, 176, 189], sively limited to pneumonia caused by the Enterobacterales
respectively. Most data are available for ceftazidime-avibactam, [196]. Subsequent investigations have demonstrated that
in part because it was the first of the novel β-lactam agents active when high-dose tigecycline is prescribed (200 mg intravenous-
against CRE to receive approval from the US Food and Drug ly as a single dose followed 100 mg intravenously every
Administration. Very limited data exist on the frequency of 12 hours) mortality differences between tigecycline and

comparator agents may no longer be evident [197–199]. Thus, Rationale
if tigecycline is prescribed for the treatment of CRE infections, Although empiric combination antibiotic therapy increases the
the panel recommends that high-dosages be administered [200] likelihood that at least 1 active therapeutic agent for patients at
(Table 1). risk for CRE infections is being administered, data do not indicate
Eravacycline MICs are generally 2- to 4-fold lower than tige- that continued combination therapy—once the β-lactam agent
cycline MICs against CRE [201]. The clinical relevance of the has demonstrated in vitro activity—offers any additional benefit
MIC distributions between these agents is unclear because of [209]. Rather, the continued use of a second agent increases the
differences in the pharmacokinetic/pharmacodynamic profile likelihood of antibiotic-associated adverse events [209].
of tigecycline and eravacycline. Fewer than 5 patients with Observational data and clinical trials comparing
CRE infections were included in clinical trials that investigated ceftazidime-avibactam, meropenem-vaborbactam, and
the efficacy of eravacycline [192, 202], and post-marketing clin- imipenem-cilastatin-relebactam to combination regimens
ical reports describing its efficacy for the treatment of CRE in- (eg, ceftazidime-avibactam versus meropenem and colistin)
fections are limited [203]. for the treatment of CRE infections have not shown the latter

Limited clinical data are also available investigating the effec- to improve clinical outcomes [124–132]. An observational
tiveness of minocycline against CRE infections [204, 205], but study compared the clinical outcomes of 165 patients receiving
data suggest a lower proportion of CRE isolates are likely to be ceftazidime-avibactam and 412 patients receiving ceftazidime-
susceptible to minocycline compared to tigecycline or eravacy- avibactam plus a second agent for the treatment of
cline. The panel suggests using minocycline with caution for KPC-producing infections [210]. Thirty-day mortality was es-
the treatment of CRE infections. Data evaluating the activity sentially identical at approximately 25% in both study arms.
of omadacycline, a tetracycline-derivative with both an intrave- Randomized trial data are not available comparing the novel
nous and oral formulation, against CRE suggests reduced po- β-lactam agents as monotherapy and as a component of
tency relative to other tetracycline derivatives and an combination therapy (eg, ceftazidime-avibactam versus
unfavorable pharmacokinetic and pharmacodynamic profile ceftazidime-avibactam and amikacin). However, based on
[50, 206–208]. The panel suggests avoiding the use of omadacy- available outcomes data, clinical experience, and known toxici-
cline for the treatment of CRE infections. ties associated with aminoglycosides, fluoroquinolones, and
polymyxins, the panel does not routinely recommend combina-
Question 8: What Is the Role of Polymyxins for the Treatment of Infections tion therapy for CRE infections when susceptibility to a pre-
Caused by CRE? ferred β-lactam agent has been demonstrated.
Recommendation: Polymyxin B and colistin should be avoided
for the treatment of infections caused by CRE. Colistin can be
considered as an alternative agent for uncomplicated CRE PSEUDOMONAS AERUGINOSA WITH
cystitis. DIFFICULT-TO-TREAT RESISTANCE
The CDC reports that 32 600 cases of multidrug-resistant

Rationale (MDR) P. aeruginosa infection occurred in patients hospital-
Observational and RCT data indicate increased mortality and ized in the United States in 2017, resulting in 2700 deaths [1].
excess nephrotoxicity associated with polymyxin-based regi- MDR P. aeruginosa is defined as P. aeruginosa not susceptible
mens relative to comparator agents [124–132]. Concerns about to at least 1 antibiotic in at least 3 antibiotic classes for which
the clinical effectiveness of polymyxins and accuracy of poly- P. aeruginosa susceptibility is generally expected: penicillins,
myxin susceptibility testing led the CLSI to eliminate a suscep- cephalosporins, fluoroquinolones, aminoglycosides, and carba-
tible category for colistin and polymyxin B [15]. The panel penems [211]. In 2018, the concept of “difficult-to-treat” resis-
recommends that these agents be avoided for the treatment tance was proposed [3]. In this guidance document, DTR is
of CRE infections, with the exception of colistin as an alterna- defined as P. aeruginosa exhibiting non-susceptibility to all of
tive agent against CRE cystitis. Polymyxin B should not be used the following: piperacillin-tazobactam, ceftazidime, cefepime,
as treatment for CRE cystitis, due to its predominantly nonre- aztreonam, meropenem, imipenem-cilastatin, ciprofloxacin,
nal clearance [107]. and levofloxacin.
Multidrug-resistant P. aeruginosa or DTR-P. aeruginosa
Question 9: What Is the Role of Combination Antibiotic Therapy for the generally evolve as a result of an interplay of multiple complex
Treatment of Infections Caused by CRE? resistance mechanisms, including decreased expression of outer
Recommendation: Combination antibiotic therapy (ie, the use membrane porins (OprD), hyperproduction of AmpC enzymes,
of a β-lactam agent in combination with an aminoglycoside, upregulation of efflux pumps, and mutations in penicillin-
fluoroquinolone, or polymyxin) is not routinely recommended binding protein targets [212, 213]. Carbapenemase production
for the treatment of infections caused by CRE. is a rare cause of carbapenem resistance in P. aeruginosa in

the United States but is identified in upward of 20% An alternative approach is to administer a novel β-lactam
of carbapenem-resistant P. aeruginosa in other regions of agent (eg, ceftolozane-tazobactam, ceftazidime-avibactam,
the world [214–216]. Treatment recommendations for imipenem-cilastatin-relebactam), selecting an agent that
DTR-P. aeruginosa infections listed below assume that in vitro tests susceptible. This approach is considered an alternative
activity of preferred and alternative antibiotics has been option to preserve the effectiveness of novel β-lactams for fu-
demonstrated. ture, increasingly antibiotic-resistant infections. However,
for patients with moderate to severe infection or with poor
Question 1: What Are Preferred Antibiotics for the Treatment of Infections source control, use of a novel β-lactam for MDR P. aerugino-
Caused by MDR P. aeruginosa? sa infections resistant to carbapenems but susceptible to non-
Recommendation: When P. aeruginosa isolates test susceptible carbapenem β-lactams is a reasonable consideration. Regardless
to traditional non-carbapenem β-lactam agents (ie, piperacillin- of the antibiotic agent administered, patients infected with
tazobactam, ceftazidime, cefepime, aztreonam), they are pre- P. aeruginosa should be closely monitored to ensure clinical
ferred over carbapenem therapy. For infections caused by P. aer- improvement as P. aeruginosa exhibits an impressive capacity

uginosa isolates not susceptible to any carbapenem agents but to acquire additional resistance mechanisms while exposed to
susceptible to traditional β-lactams, the administration of a tradi- antibiotic therapy.
tional agent as high-dose extended-infusion therapy is suggested,
after antibiotic susceptibility testing results are confirmed. For pa- Question 2: What Are Preferred Antibiotics for the Treatment of
tients with moderate to severe disease or poor source control with Uncomplicated Cystitis Caused by DTR-P. aeruginosa?
P. aeruginosa isolates resistant to carbapenems but susceptible Recommendation: Ceftolozane-tazobactam, ceftazidime-
to traditional β-lactams, use of a novel β-lactam agent that tests avibactam, imipenem-cilastatin-relebactam, cefiderocol, or
susceptible (eg, ceftolozane-tazobactam, ceftazidime-avibactam, a single-dose of an aminoglycoside are the preferred treat-
imipenem-cilastatin-relebactam) is also a reasonable treatment ment options for uncomplicated cystitis caused by DTR-P.
option. aeruginosa.
Rationale Rationale
In general, when a P. aeruginosa isolate tests susceptible to mul- Ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-
tiple traditional β-lactam agents (ie, piperacillin-tazobactam, cilastatin-relebactam, and cefiderocol are preferred treatment
ceftazidime, cefepime, aztreonam) or fluoroquinolones (ie, cip- options for uncomplicated DTR-P. aeruginosa cystitis, based on
rofloxacin, levofloxacin), the panel prefers these agents be pre- RCTs showing non-inferiority of these agents to common com-
scribed over carbapenem therapy in an attempt to preserve the parator agents for the treatment of UTIs [101, 103–105, 224].
activity of carbapenems for future, increasingly drug-resistant Data are insufficient to favor 1 of these agents over the others
infections. for the treatment of uncomplicated cystitis, and available trials
P. aeruginosa isolates not susceptible to a carbapenem agent generally do not include patients infected by pathogens with
(eg, meropenem or imipenem-cilastatin MICs ≥4 mcg/mL) DTR phenotypes. Additional information comparing these
but susceptible to other traditional non-carbapenem β-lactam agents is described in Question 4.
agents (eg, piperacillin-tazobactam MIC ≤16/4 mcg/mL, cefta- A single dose of an aminoglycoside is also a preferred treat-
zidime ≤8 mcg/mL, cefepime ≤8 mcg/mL, or aztreonam ment option. Aminoglycosides are nearly exclusively eliminat-
≤8 mcg/mL) [15] constitute approximately 20–60% of ed by the renal route in their active form. A single intravenous
carbapenem-resistant P. aeruginosa isolates [217–223]. dose is generally effective for uncomplicated cystitis, with min-
This phenotype is generally due to lack of or limited production imal toxicity, but robust trial data are lacking [28]. Plazomicin
of OprD, which normally facilitates entry of carbapenem agents is unlikely to provide any incremental benefit against DTR-P.
into bacteria [219–222]. Comparative effectiveness studies to aeruginosa if resistance to all other aminoglycosides is demon-
guide treatment decisions for infections caused by P. aeruginosa strated [225].
resistant to carbapenems but susceptible to other traditional Colistin, but not polymyxin B, is an alternate consider-
non-carbapenem β-lactams are not available. When confronted ation for treating DTR-P. aeruginosa cystitis as it converts
with these scenarios, the panel suggests repeating susceptibility to its active form in the urinary tract [106]. Clinicians should
testing to confirm antibiotic MICs. If the isolate remains suscep- remain cognizant of the associated risk of nephrotoxicity.
tible to a traditional non-carbapenem β-lactam (eg, cefepime) The panel does not recommend the use of oral fosfomycin
on repeat testing, the panel’s preferred approach is to administer for DTR-P. aeruginosa cystitis as it is associated with a
the non-carbapenem agent as high-dose extended-infusion high likelihood of clinical failure [18, 226]. This is in part
therapy (eg, cefepime 2 g IV every 8 hours, infused over due to the presence of the fosA gene, which is intrinsic to
3 hours) (Table 1). P. aeruginosa [29].

Question 3: What Are Preferred Antibiotics for the Treatment of its slightly higher likelihood of activity against DTR-P. aerugi-
Pyelonephritis and Complicated Urinary Tract Infections Caused by nosa compared to other novel β-lactam-β-lactamase inhibitors.
DTR-P. aeruginosa?
Neither ceftazidime nor imipenem is active against DTR-P. aer-
Recommendation: Ceftolozane-tazobactam, ceftazidime-
uginosa. Avibactam and relebactam expand activity of these
avibactam, imipenem-cilastatin-relebactam, and cefiderocol
agents mainly through inhibition of AmpC, but other complex
are the preferred treatment options for pyelonephritis and
resistance mechanisms are unlikely to be impacted. Regional
cUTI caused by DTR-P. aeruginosa.
differences in susceptibility estimates across the newer agents
likely exist. The panel recommends always obtaining antibiotic
Rationale
susceptibility testing results for DTR-P. aeruginosa infections
Ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-
to guide treatment decisions.
cilastatin-relebactam, and cefiderocol are preferred treatment
Clinical trials comparing effectiveness across the newer
options for DTR-P. aeruginosa pyelonephritis and cUTI, based
agents are not available, but observational data and subgroup
on RCTs showing non-inferiority of these agents to common
analysis from clinical trial data provide insights into the ef-
comparator agents [101, 103–105, 224]. Data are insufficient

fectiveness of the newer β-lactam agents compared to tradi-
to favor 1 of these agents over the others for the treatment of
tional anti-pseudomonal regimens. An observational study
pyelonephritis and cUTI, and available trials generally do
including 200 patients with MDR P. aeruginosa compared
not include patients infected by pathogens with DTR pheno-
the outcomes of patients receiving ceftolozane-tazobactam
types. Additional information comparing these agents is de-
versus polymyxin or aminoglycoside-based therapy [269].
scribed in Question 4.
Favorable clinical outcomes were observed in 81% of patients
In patients in whom the potential for nephrotoxicity is
receiving ceftolozane-tazobactam versus 61% of patients re-
deemed acceptable, once-daily aminoglycosides are an alterna-
ceiving polymyxin- or aminoglycoside-based therapy; this
tive option [38]. Plazomicin is unlikely to provide any incre-
difference achieved statistical significance. An RCT including
mental benefit against DTR-P. aeruginosa if resistance to all
24 patients infected with imipenem-non-susceptible P. aeru-
other aminoglycosides is demonstrated [225].
ginosa identified a favorable clinical response in 81% of patients
Question 4: What Are Preferred Antibiotics for the Treatment of Infections
receiving imipenem-cilastatin-relebactam compared to 63% re-
Outside of the Urinary Tract Caused by DTR-P. aeruginosa? ceiving imipenem-cilastatin in combination with colistin [127].
Recommendation: Ceftolozane-tazobactam, ceftazidime-avibactam, Although not achieving statistical significance, potentially due
and imipenem-cilastatin-relebactam, as monotherapy, are preferred to the small sample size, the numerical differences suggest im-
options for the treatment of infections outside of the urinary tract proved outcomes with use of imipenem-cilastatin-relebactam
caused by DTR-P. aeruginosa. over more traditional regimens. Rigorous data investigating
the activity of ceftazidime-avibactam against comparators are
Rationale lacking. However, pooled data from 5 RCTs explored differ-
Ceftolozane-tazobactam, ceftazidime-avibactam, and imipenem- ences in clinical responses for patients with MDR P. aerugino-
cilastatin-relebactam, as monotherapy, are preferred options for sa infections receiving ceftazidime-avibactam versus more
the treatment of infections outside of the urinary tract, based on traditional regimens with a favorable clinical response ob-
in vitro activity [139, 141, 177, 227–268], observational studies served in 57% (32 of 56 patients) versus 54% (21 of 39) of pa-
[269], and clinical trial data [101, 127, 270–276]. The vast majority tients in the 2 treatment arms, respectively [279]. An
of patients in clinical trials receiving the novel β-lactam-β-lacta- important limitation to these data were that only 66% of iso-
mase inhibitors were not infected with DTR-P. aeruginosa. lates were susceptible to ceftazidime-avibactam making inter-
Summarizing international surveillance data, ceftolozane- pretation of the results challenging [279].
tazobactam [227, 229, 230, 232–242, 253], ceftazidime-avibac- Cefiderocol is recommended as an alternative treatment op-
tam [228, 241–253], and imipenem-cilastatin-relebactam tion for DTR-P. aeruginosa infections outside of the urine.
[139, 141, 177, 253–268] are active against approximately Cefiderocol is a synthetic conjugate composed of a cephalospo-
76%, 74%, and 69% of carbapenem-resistant P. aeruginosa iso- rin moiety and a catechol-type siderophore, which binds to
lates, respectively, with lower percent susceptibilities exhibited iron and facilitates bacterial cell entry using active iron trans-
by isolates from patients with cystic fibrosis [277, 278]. porters [143]. Once inside the periplasmic space, the cephalospo-
Available surveillance data generally represent time periods be- rin moiety dissociates from iron and binds primarily to
fore the novel agents were used clinically and likely overesti- penicillin-binding protein 3 to inhibit bacterial cell wall synthesis
mate susceptibility percentages observed in clinical practice. [280]. Combining data from 1500 carbapenem-non-susceptible
Ceftolozane does not rely on an inhibitor to restore susceptibil- P. aeruginosa isolates in surveillance studies, over 97% of isolates
ity to an otherwise inactive drug (ie, ceftolozane has indepen- exhibited susceptibility to cefiderocol (ie, MICs ≤4 mcg/mL)
dent activity against DTR-P. aeruginosa), which may explain [133, 281–286]. Similar to the novel β-lactam-β-lactamase

inhibitors, percent susceptibility to cefiderocol is likely to be re- [303, 304]. The reader is referred to comprehensive review ar-
duced after widespread use of this agent. ticles on this topic for a more complete understanding of the
An RCT compared the outcomes of patients with infections mechanisms of resistance to the novel β-lactams [143, 186, 187].
due to carbapenem-resistant organisms treated with cefiderocol Based on available data thus far, the emergence of resis-
versus best available therapy, which was largely polymyxin-based tance of P. aeruginosa to novel β-lactams appears most con-
therapy [105]. The trial included 22 unique patients with 29 CR-P. cerning for ceftolozane-tazobactam and ceftazidime-avibactam.
aeruginosa infections, including 6 patients with UTIs, 17 patients Cross-resistance between these agents is high because of sim-
with pneumonia, and 6 patients with bloodstream infections ilar mechanisms of resistance. In a cohort of 28 patients with
[287]. Mortality at the end of therapy was 18% in both the cefider- DTR-P. aeruginosa infections treated with ceftolozane-
ocol and best available therapy arms for patients infected with P. tazobactam, 50% of patients were infected with subsequent
aeruginosa. This trial suggests that cefiderocol performs as well as DTR-P. aeruginosa isolates no longer susceptible to
agents that were the mainstay of treatment against DTR-P. aeru- ceftolozane-tazobactam [299]. Remarkably, over 80% of pa-
ginosa in the past such as combinations of extended-infusion tients with index isolates susceptible to ceftazidime-avibactam

meropenem, polymyxins, and aminoglycosides but may not be had subsequent isolates with high-level resistance to
associated with improved outcomes, as has been observed with ceftazidime-avibactam after ceftolozane-tazobactam expo-
some of the newer β-lactam-β-lactamase inhibitors [127, 269]. sure, and in the absence of ceftazidime-avibactam exposure.
Despite the high likelihood of cefiderocol activity against Another cohort study including 23 patients with index and sub-
DTR-P. aeruginosa, the panel recommends cefiderocol as an al- sequent P. aeruginosa isolates after ceftolozane-tazobactam de-
ternative option when inactivity, intolerance, or unavailability scribed a similar experience [298]. Treatment-emergent
precludes the use of the newer β-lactam-β-lactamase inhibitors. mutations in ampC were identified in 79% of paired isolates.
Limited data on the frequency of emergence of resistance to
Question 5: What Is the Likelihood of the Emergence of Resistance of imipenem-cilastatin-relebactam exist. Whether this is indicative
DTR-P. aeruginosa Isolates to the Newer β-Lactam Agents When Used to of the successful properties of this combination or the result of
Treat DTR-P. aeruginosa infections? its limited clinical use is not clear. Similarly, estimates of the fre-
Recommendation: The emergence of resistance is a concern quency of the emergence of resistance of P. aeruginosa to cefi-
with all of the novel β-lactams used to treat DTR-P. aeruginosa derocol since its clinical introduction are not yet available but
infections, but the frequency appears to be the highest for in a clinical trial, 3 of 12 carbapenem-resistant isolates had at
ceftolozane-tazobactam and ceftazidime-avibactam. least 4-fold increases in cefiderocol MICs (though not necessar-
ily frank resistance) after exposure to this agent [105].
Rationale The panel recommends always repeating antibiotic suscepti-
As with most antibiotic agents, treatment of DTR-P. aeruginosa bility testing for the newer β-lactams when a patient previously
with any of the newer β-lactam agents (ie, ceftolozane-tazobactam, infected with a DTR-P. aeruginosa presents with a sepsis-like
ceftazidime-avibactam, imipenem-cilastatin-relebactam, or picture suggestive of a new or relapsed infection. Furthermore,
cefiderocol) increases the likelihood that subsequent infections if a patient was recently treated with ceftolozane-tazobactam
will no longer be effectively treated with these agents. The or ceftazidime-avibactam and presents to medical care with
emergence of resistance to ceftolozane-tazobactam most com- symptoms of infection, the panel suggests considering use of a
monly occurs because of amino acid substitutions, insertions, different novel β-lactam agent at least until culture and suscept-
or deletions in Pseudomonas-derived cephalosporinase (PDC), ibility data are available.
the chromosomally encoded class C β-lactamase of P. aerugi-
nosa, commonly referred to as “the pseudomonal AmpC” [8, Question 6: What Is the Role of Combination Antibiotic Therapy for the
231, 288–299]. These alterations occur most commonly in or Treatment of Infections Caused by DTR-P. aeruginosa?
adjacent to a particular region of the PDC known as the “ome- Recommendation: Combination antibiotic therapy is not rou-
ga loop.” Similarly, acquired resistance of P. aeruginosa to tinely recommended for infections caused by DTR-P. aeruginosa
ceftazidime-avibactam is most frequently the result of alter- if in vitro susceptibility to a first-line antibiotic (ie, ceftolozane-
ations in PDCs [288, 290, 291, 293, 296, 298–301]. tazobactam, ceftazidime-avibactam, or imipenem-cilastatin-
Mechanisms contributing to P. aeruginosa resistance to relebactam) has been confirmed.
imipenem-cilastatin-relebactam are less clear and may be related
to increased production of PDCs in combination with loss of Rationale
OprD [177, 302]. A number of diverse mechanisms of P. aerugi- Although empiric combination antibiotic therapy (eg, the addi-
nosa resistance to cefiderocol have been described including mu- tion of an aminoglycoside to a β-lactam agent) to broaden the
tations in the TonB-dependent iron transport system [179–181, likelihood of at least 1 active therapeutic agent for patients at
303] or amino acid changes in the AmpC β-lactamases risk for DTR-P. aeruginosa infections is reasonable, data do

not indicate that continued combination therapy—once the Rationale
β-lactam agent has demonstrated in vitro activity—offers any There have been conflicting findings for the clinical effectiveness
additional benefit over monotherapy with the β-lactam [209]. of nebulized antibiotics for the treatment of Gram-negative
Rather, the continued use of a second agent increases the like- pneumonia in observational studies [311–338]. Three RCTs
lihood of antibiotic-associated adverse events [209]. compared the outcomes of patients with gram-negative
Observational data and clinical trials that have compared ventilator-associated pneumonia comparing nebulized anti-
ceftolozane-tazobactam and imipenem-cilastatin-relebactam, biotics versus placebo. All 3 trials allowed for the use of sys-
usually given as monotherapy, to combination regimens for temic antibiotics, at the discretion of the treating clinician.
drug-resistant P. aeruginosa infections have not shown the latter In brief, 1 trial compared the outcomes of 100 adults with
to have added value [127, 269]. Randomized trial data comparing pneumonia (34% caused by P. aeruginosa) treated with nebu-
ceftolozane-tazobactam, ceftazidime-avibactam, or imipenem- lized colistin versus placebo [339]; a second trial compared the
cilastatin-relebactam as monotherapy and as a component of outcomes of 142 adults with pneumonia (22% caused by P.
combination therapy are not available (eg, ceftazidime-avibactam aeruginosa) treated with nebulized amikacin/fosfomycin ver-

versus ceftazidime-avibactam and amikacin). Based on existing sus placebo [340]; and the third trial compared the outcomes
outcomes data, clinical experience, and known toxicities associat- of 508 adults with pneumonia (32% caused by P. aeruginosa)
ed with aminoglycosides and polymyxins, the panel does not rec- treated with nebulized amikacin versus placebo [341]. None of
ommend that combination therapy be routinely administered for the 3 clinical trials demonstrated improved clinical outcomes
DTR-P. aeruginosa infections when susceptibility to a preferred or a survival benefit with the use of nebulized antibiotics com-
β-lactam agent has been demonstrated. pared with placebo for the treatment of ventilator-associated
If no preferred agent demonstrates activity against DTR-P. aer- pneumonia, including in subgroup analyses of drug-resistant
uginosa, an aminoglycoside (if susceptibility is demonstrated) can pathogens [339–341].
be considered in combination with either ceftolozane-tazobactam, Reasons for the lack of clinical benefit in these trials are un-
ceftazidime-avibactam, or imipenem-cilastatin-relebactam, clear. In a pharmacokinetic-pharmacodynamic modeling
preferentially selecting the β-lactam-β-lactamase inhibitor study, aerosolized delivery of the prodrug of colistin to critically
agent for which the MIC is closest to its susceptibility break- ill patients achieved high active drug levels in epithelial lining
point. For example, if ceftolozane-tazobactam and ceftazidime- fluid of the lungs [342]. However, it is likely that nebulized an-
avibactam MICs against a DTR-P. aeruginosa isolate are tibiotics do not achieve sufficient penetration and/or distribu-
both .128/4 mcg/mL (highly resistant) and the imipenem- tion throughout lung tissue to exert significant bactericidal
cilastatin-relebactam MIC is 4/4 mcg/mL (intermediate cate- activity [343], likely due in part to the use of parenteral formu-
gory), imipenem-cilastatin-relebactam in combination with lations not specifically designed for inhalation in suboptimal
an active aminoglycoside is favored. Data are lacking demon- delivery devices such as jet nebulizers [344, 345]. Professional
strating a benefit to this approach, and it should be consid- societies have expressed conflicting views regarding the role
ered as a last resort. Similarly, data are lacking whether this of nebulized antibiotics as adjunctive therapy to intravenous
approach will yield more favorable clinical outcomes com- antibiotics [346–348]. The panel recommends against the use
pared to cefiderocol, either as monotherapy or combination of nebulized antibiotics as adjunctive therapy for DTR-P. aeru-
therapy. This approach is suggested as it may increase the ginosa pneumonia due to the lack of benefit observed in clinical
likelihood that at least 1 active agent is being included in trials, concerns regarding unequal distribution in infected
the treatment regimen. lungs, and concerns for respiratory complications such as bron-
If no aminoglycoside demonstrates in vitro activity, polymyx- choconstriction in 10–20% of patients receiving aerosolized an-
in B can be considered in combination with the β-lactam-β- tibiotics [349].
lactamase inhibitor. Polymyxin B is preferred over colistin for
non-urinary tract infections because (1) it is not administered as
CONCLUSIONS
a prodrug and therefore can achieve more reliable plasma concen-
trations than colistin, and (2) it has a reduced risk of nephrotox- The field of AMR is dynamic and rapidly evolving, and the
icity, although limitations across studies preclude accurate treatment of antimicrobial-resistant infections will continue
determination of the differential risk of nephrotoxicity [305–310]. to challenge clinicians. As newer antibiotics against resistant
pathogens are incorporated into clinical practice, we are learn-
Question 7: What Is the Role of Nebulized Antibiotics for the Treatment of ing more about their effectiveness and propensity to resistance.
Respiratory Infections Caused by DTR-P. aeruginosa? This treatment guidance focusing on ESBL-E, CRE, and
Recommendation: The panel does not recommend the routine DTR-P. aeruginosa will be updated annually and is available
addition of nebulized antibiotics for the treatment of respirato- at: https://www.idsociety.org/practice-guideline/amr-guidance/.
ry infections caused by DTR-P. aeruginosa. A second AMR treatment guidance focusing on the treatment

of infections caused by AmpC-producing Enterobacterales, 4. Gupta K, Hooton TM, Naber KG, et al. International clinical practice guidelines
for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a
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Acknowledgments. The authors express their sincere gratitude to the
tions in U.S. hospitalized patients, 2012–2017. N Engl J Med 2020; 382:1309–19.
Infectious Diseases Society of America (IDSA) for organizing the develop-
7. Tamma PD, Sharara SL, Pana ZD, et al. Molecular epidemiology of ceftriaxone
ment of this treatment guidance.
non-susceptible enterobacterales isolates in an academic medical center in the
Potential conflicts of interest. The following list is a reflection of what United States. Open Forum Infect Dis 2019; 6:ofz353.
has been reported to IDSA. To provide thorough transparency, IDSA re- 8. Haidar G, Philips NJ, Shields RK, et al. Ceftolozane-tazobactam for the treatment
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is determined by a review process which includes assessment by the Board 9. Tamma PD, Smith TT, Adebayo A, et al. Prevalence of blaCTX-M genes in gram-
of Directors liaison to the Standards and Practice Guidelines Committee negative bloodstream isolates across 66 hospitals in the United States. J Clin
Microbiol 2021; 59: e00127-21.

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Diseases, Veterans Health Administration, Shionogi, VenatoRx, Merck, tection in the presence of plasmid-mediated AmpC in Escherichia coli clinical
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served as an advisor for Rempex and Antimicrobial Resistance ceftriaxone-resistant Enterobacterales. JAC Antimicrob Resist 2021; 3:dlab020.
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received research funding from the National Institutes of Health and
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Clinical Infectious Diseases

Infectious Diseases Society of America 2022 Guidance

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