Treatment of Extended Spectrum β-lactamase Producing Enterobacterales (ESBL-E), Carbapenem-Resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with Difficult-to-Treat Resistance (DTRP. aeruginosa)

Publication Date: April 19, 2022
Last Updated: May 10, 2022

Extended-spectrum β-lactamase-Producing Enterobacterales

Nitrofurantoin and trimethoprim-sulfamethoxazole are preferred treatment options for uncomplicated cystitis caused by ESBL-E.
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Ertapenem, meropenem, imipenem-cilastatin, ciprofloxacin, levofloxacin, or trimethoprim-sulfamethoxazole are preferred treatment options for pyelonephritis and cUTIs caused by ESBL-E.
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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 fluoroquinolones or trimethoprim-sulfamethoxazole should be considered, if susceptibility is demonstrated.
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If piperacillin-tazobactam was initiated as empiric therapy for uncomplicated cystitis caused by an organism later identified as an ESBL-E and clinical improvement occurs, no change or extension of antibiotic therapy is necessary. The panel suggests carbapenems, fluoroquinolones, or trimethoprim-sulfamethoxazole rather than piperacillin-tazobactam for the treatment of ESBL-E pyelonephritis and cUTI, with the understanding that the risk of clinical failure with piperacillin-tazobactam may be low. Piperacillin-tazobactam is not recommended for the treatment of infections outside of the urinary tract caused by ESBL-E, even if susceptibility to piperacillin-tazobactam is demonstrated.
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Cefepime is not recommended for the treatment of non-urinary infections caused by ESBL-E, even if susceptibility to the agent is demonstrated. If cefepime was initiated as empiric therapy for uncomplicated cystitis caused by an organism later identified as an ESBLE and clinical improvement occurs, no change or extension of antibiotic therapy is necessary. The panel recommends avoiding cefepime for the treatment of pyelonephritis and cUTI. Cefepime is also not recommended for the treatment of infections outside of the urinary tract caused by ESBL-E, even if susceptibility to cefepime is demonstrated.
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Cephamycins are not recommended for the treatment of ESBL-E infections until more clinical outcomes data using cefoxitin or cefotetan are available and optimal dosing has been defined.
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Carbapenem-Resistant Enterobacterales

Ciprofloxacin, levofloxacin, trimethoprim-sulfamethoxazole, nitrofurantoin, or a single-dose of an aminoglycoside are preferred treatment options for uncomplicated cystitis caused by CRE. Standard infusion meropenem is a preferred treatment option for cystitis caused by CRE resistant to ertapenem (i.e., ertapenem MICs ≥2 mcg/mL) but susceptible to meropenem (i.e., meropenem MICs ≤1 mcg/mL), when carbapenemase testing results are either not available or negative. If none of the preferred agents are active, ceftazidimeavibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, or cefiderocol are alternative options for uncomplicated CRE cystitis.
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Ciprofloxacin, levofloxacin, and trimethoprim-sulfamethoxazole are preferred treatment options for pyelonephritis and cUTI caused by CRE if susceptibility is demonstrated. Extended-infusion meropenem is a preferred treatment option for pyelonephritis and cUTIs caused by CRE resistant to ertapenem (i.e., ertapenem MICs ≥2 mcg/mL) but susceptible to meropenem (i.e., meropenem MICs ≤1 mcg/mL), when carbapenemase testing results are either not available or negative. Ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, and cefiderocol are also preferred treatment options for pyelonephritis and cUTIs caused by CRE resistant to both ertapenem and meropenem.
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Extended-infusion meropenem is the preferred treatment for infections outside of the urinary tract caused by CRE resistant to ertapenem (i.e., ertapenem MICs ≥2 mcg/mL) but susceptible to meropenem (i.e., meropenem MICs ≤1 mcg/mL), when carbapenemase testing results are either not available or negative.
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Ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-cilastatinrelebactam are the preferred treatment options for infections outside of the urinary tract caused by CRE resistant to both ertapenem (i.e., ertapenem MICs ≥2 mcg/mL) and meropenem (i.e., meropenem MICs ≥4 mcg/mL), when carbapenemase testing results are either not available or negative. For patients with CRE infections who within the previous 12 months have received medical care in countries with a relatively high prevalence of metallo-β-lactamaseproducing organisms or who have previously had a clinical or surveillance culture where a metallo-β-lactamase-producing isolate was identified, preferred treatment options include the combination of ceftazidime-avibactam plus aztreonam, or cefiderocol as monotherapy, if carbapenemase testing results are not available.
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Meropenem-vaborbactam, ceftazidime-avibactam, and imipenem-cilastatinrelebactam are preferred treatment options for KPC-producing infections outside of the urinary tract. Ceftazidime-avibactam in combination with aztreonam, or cefiderocol as monotherapy, are preferred treatment options for NDM and other metallo-β-lactamase-producing infections. Ceftazidime-avibactam is the preferred treatment option for OXA-48-like-producing infections.
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The emergence of resistance is a concern with all of the novel β-lactams used to treat CRE infections, but the frequency appears to be the highest for ceftazidimeavibactam.
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Although β-lactam agents remain preferred treatment options for CRE infections, tigecycline and eravacycline are alternative options when β-lactam agents are either not active or unable to be tolerated. The tetracycline derivatives are not recommended as monotherapy for the treatment of CRE urinary tract infections or bloodstream infections.
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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 cystitis.
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Combination antibiotic therapy (i.e., the use of a β-lactam agent in combination with an aminoglycoside, fluoroquinolone, or polymyxin) is not routinely recommended for the treatment of infections caused by CRE.
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Pseudomonas aeruginosa with Difficult-to-Treat Resistance

When P. aeruginosa isolates test susceptible to traditional non-carbapenem β-lactam agents (i.e., piperacillin-tazobactam, ceftazidime, cefepime, aztreonam), they are preferred over carbapenem therapy. For infections caused by P. aeruginosa isolates not susceptible to any carbapenem agents but susceptible to traditional β-lactams, the administration of a traditional agent as high-dose extended-infusion therapy is suggested, after antibiotic susceptibility testing results are confirmed. For patients with moderate to severe disease or poor source control with P. aeruginosa isolates resistant to carbapenems but susceptible to traditional β-lactams, use of a novel β-lactam agent that tests susceptible (e.g., ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-cilastatin-relebactam) is also a reasonable treatment option.
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Ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-cilastatinrelebactam, cefiderocol, or a single-dose of an aminoglycoside are the preferred treatment options for uncomplicated cystitis caused by DTR-P. aeruginosa.
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Ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-cilastatinrelebactam, and cefiderocol are the preferred treatment options for pyelonephritis and cUTI caused by DTR-P. aeruginosa.
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Ceftolozane-tazobactam, ceftazidime-avibactam, and imipenem-cilastatinrelebactam, as monotherapy, are preferred options for the treatment of infections outside of the urinary tract caused by DTR-P. aeruginosa.
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The emergence of resistance is a concern with all of the novel β-lactams used to treat DTR-P. aeruginosa infections, but the frequency appears to be the highest for ceftolozane-tazobactam and ceftazidime-avibactam.
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Combination antibiotic therapy is not routinely recommended for infections caused by DTR-P. aeruginosa if in vitro susceptibility to a first-line antibiotic (i.e., ceftolozanetazobactam, ceftazidime-avibactam, or imipenem-cilastatin-relebactam) has been confirmed.
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The panel does not recommend the routine addition of nebulized antibiotics for the treatment of respiratory infections caused by DTR-P. aeruginosa.
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Recommendation Grading

Abbreviations

  • CRE: Extended Spectrum β-lactamase Producing Enterobacterales
  • ESBL-E: Extended Spectrum β-lactamase Producing Enterobacterales

Overview

Title

Treatment of Extended Spectrum β-lactamase Producing Enterobacterales (ESBL-E), Carbapenem-Resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with Difficult-to-Treat Resistance (DTRP. aeruginosa)

Authoring Organization

Publication Month/Year

April 19, 2022

Last Updated Month/Year

February 12, 2024

Supplemental Implementation Tools

Document Type

Consensus

Country of Publication

US

Inclusion Criteria

Male, Female, Adolescent, Adult, Child, Infant

Health Care Settings

Ambulatory, Hospital, Outpatient

Intended Users

Nurse, nurse practitioner, physician, physician assistant

Scope

Management

Diseases/Conditions (MeSH)

D006090 - Gram-Negative Bacteria, D016905 - Gram-Negative Bacterial Infections

Keywords

Antibiotic Resistance, antibiotics, gram-negative, Carbapenem-Resistant Enterobacterales

Source Citation

Tamma PD, Aitken SL, Bonomo RA, Mathers AJ, van Duin D, Clancy CJ. 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). Clin Infect Dis. 2022 Apr 19:ciac268. doi: 10.1093/cid/ciac268. Epub ahead of print. PMID: 35439291.