Treatment of Antimicrobial Resistant Gram-Negative Infections
Publication Date: June 7, 2023
Last Updated: January 19, 2024
Recommendations
Extended-Spectrum β-Lactamase-Producing Enterobacterales
Nitrofurantoin and TMP-SMX are preferred treatment options for uncomplicated cystitis caused by ESBL-E. Ciprofloxacin, levofloxacin, and carbapenems are alternative agents for uncomplicated cystitis caused by ESBL-E. Although effective, their use is discouraged when nitrofurantoin or TMP-SMX are active. Single dose aminoglycosides and oral fosfomycin (for E. coli only) are also alternative treatments for uncomplicated cystitis caused by ESBL-E.
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TMP-SMX, ciprofloxacin, or levofloxacin are preferred treatment options for pyelonephritis and cUTIs caused by ESBL-E. Ertapenem, meropenem, and imipenem-cilastatin are preferred agents when resistance or toxicities preclude the use of TMP-SMX or fluoroquinolones. Aminoglycosides for a full treatment course are an alternative option for the treatment of ESBL-E pyelonephritis or cUTI.
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Meropenem, imipenem-cilastatin, or ertapenem are preferred for the treatment of infections outside of the urinary tract caused by ESBL-E. For patients who are critically ill and/or experiencing hypoalbuminemia, meropenem or imipenem-cilastatin are the preferred carbapenems. After appropriate clinical response is achieved, transitioning to oral trimethoprim-sulfamethoxazole, ciprofloxacin, or levofloxacin 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 TMP-SMX, ciprofloxacin, levofloxacin, or carbapenems rather than piperacillin-tazobactam for the treatment of ESBL-E pyelonephritis and cUTI, with the understanding that some data suggest the risk of clinical failure with piperacillin-tazobactam may be low. Piperacillin-tazobactam is not suggested 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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If cefepime 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 avoiding cefepime for the treatment of pyelonephritis and cUTI. Cefepime is also not suggested 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 suggested 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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The panel suggests that ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, and cefiderocol be preferentially reserved for treating infections caused by organisms exhibiting carbapenem resistance. The panel suggests against the use of ceftolozane-tazobactam for the treatment of ESBL-E infections, with the possible exception of polymicrobial infections.
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AmpC β-lactamase-Producting Enterobacterales
Enterobacter cloacae complex, Klebsiella aerogenes, and Citrobacter freundii are the most common Enterobacterales at moderate to high risk for clinically significant AmpC production.
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Several β-lactam antibiotics are at relatively high risk of inducing ampC genes. Both the ability to induce ampC genes and the inability to withstand AmpC hydrolysis should inform antibiotic decision-making.
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Cefepime is suggested for the treatment of infections caused by organisms at moderate to high risk of significant AmpC production (i.e., E. cloacae complex, K. aerogenes, and C. freundii). Limited data suggest a carbapenem may be preferred for infections caused by these organisms when the cefepime MIC is ≥4 µg/mL, assuming carbapenem susceptibility is demonstrated, as ESBL co-production may be present, but data continue to evolve.
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Ceftriaxone (or cefotaxime or ceftazidime) is not suggested for the treatment of invasive infections caused by organisms at moderate to high risk of clinically significant AmpC production (e.g., E. cloacae complex, K. aerogenes, and C. freundii). Ceftriaxone is a reasonable for uncomplicated cystitis caused by these organisms when susceptibility is demonstrated.
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Piperacillin-tazobactam is not suggested for the treatment of serious infections caused by Enterobacterales at moderate to high risk of clinically significant inducible AmpC production.
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The panel suggests that ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, and cefiderocol be preferentially reserved for treating infections caused by organisms exhibiting carbapenem resistance. The panel does not suggest the use of ceftolozane-tazobactam as a treatment option for AmpC-E infections, with the possible exception of polymicrobial infections.
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Nitrofurantoin or TMP-SMX are preferred treatment options for uncomplicated AmpC-E cystitis. Aminoglycosides are alternative treatments for uncomplicated cystitis, pyelonephritis, and cUTI caused by AmpC-E. TMP-SMX or fluoroquinolones can be considered for the treatment of invasive infections caused by organisms at moderate to high risk of clinically significant AmpC production.
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Carbapenem-Resistant Enterobacterales (CRE)
For infections caused by Enterobacterales isolates that exhibit susceptibility to meropenem and imipenem (i.e., MICs ≤1 µg/mL), but are not susceptible to ertapenem (i.e., MICs ≥1 µg/mL), the use of extended-infusion meropenem (or imipenem-cilastatin) is suggested, assuming no carbapenemase has been identified.
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Nitrofurantoin, TMP-SMX, ciprofloxacin, or levofloxacin are preferred treatment options for uncomplicated cystitis caused by CRE, although the likelihood of susceptibility to any of these agents is low. A single dose of an aminoglycoside, oral fosfomycin (for E. coli only), colistin, ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, cefiderocol, are alternative treatment options for uncomplicated cystitis caused by CRE.
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TMP-SMX, ciprofloxacin, or levofloxacin are preferred treatment options for pyelonephritis and cUTI caused by CRE, if susceptibility is demonstrated. Ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, and cefiderocol are also preferred treatment options for pyelonephritis and cUTIs. Aminoglycosides are alternative treatment options.
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Ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-cilastatin-relebactam are the preferred treatment options for infections outside of the urinary tract caused by CRE, 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-lactamase-producing 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, while awaiting AST results to the novel β-lactam agents and carbapenemase testing results.
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Meropenem-vaborbactam, ceftazidime-avibactam, and imipenem-cilastatin-relebactam are preferred treatment options for KPC-producing infections. Cefiderocol is an alternative option.
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Ceftazidime-avibactam in combination with aztreonam, or cefiderocol as monotherapy, are preferred treatment options for NDM and other metallo-β-lactamase-producing infections.
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Ceftazidime-avibactam is the preferred treatment option for OXA-48-like-producing infections. Cefiderocol is an alternative treatment option.
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The emergence of resistance is a concern with all β-lactams used to treat CRE infections. Available data suggest the frequency may be highest for ceftazidime-avibactam.
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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 suggested for the treatment of CRE urinary tract infections or bloodstream infections.
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Polymyxin B and colistin are not suggested 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, tetracycline, or polymyxin) is not suggested 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 both traditional non-carbapenem β-lactam agents (i.e., piperacillin-tazobactam, ceftazidime, cefepime, aztreonam) and carbapenems, the former are preferred over carbapenem therapy. For infections caused by P. aeruginosa isolates not susceptible to any carbapenem agent but susceptible to traditional β-lactams, the administration of a traditional agent as high-dose extended-infusion therapy is suggested, and repeat AST is encouraged. For critically ill patients or those with 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 approach.
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Ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-cilastatin-relebactam, and cefiderocol are the preferred treatment options for uncomplicated cystitis caused by DTR-P. aeruginosa. A single-dose of tobramycin or amikacin is an alternative treatment for uncomplicated cystitis caused by DTR-P. aeruginosa.
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Ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-cilastatin-relebactam, 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-cilastatin-relebactam are preferred options for the treatment of infections outside of the urinary tract caused by DTR-P. aeruginosa. Cefiderocol is an alternative treatment option for infections outside of the urinary tract caused by DTR-P. aeruginosa.
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For patients infected with DTR-P. aeruginosa isolates that are metallo-β-lactamase producing, the preferred treatment is cefiderocol.
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The emergence of resistance is a concern with all β-lactams used to treat DTR-P. aeruginosa infections. Available data suggest the frequency may be the highest for ceftolozane-tazobactam and ceftazidime-avibactam.
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Combination antibiotic therapy is not suggested for infections caused by DTR-P. aeruginosa if susceptibility to ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-cilastatin-relebactam, or cefiderocol has been confirmed.
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The panel does not suggest the use of nebulized antibiotics for the treatment of respiratory infections caused by DTR-P. aeruginosa.
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Carbapenem-resistant Acinetobacter baumannii
The use of high-dose ampicillin-sulbactam (total daily dose of 6-9 grams of the sulbactam component) in combination with at least one other agent is suggested for the treatment of CRAB infections.
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Combination therapy with at least two active agents, whenever possible, is suggested for the treatment of CRAB infections, at least until clinical improvement is observed, because of the limited clinical data supporting any single antibiotic agent.
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High-dose ampicillin-sulbactam is suggested as a component of combination therapy for CRAB, regardless of whether susceptibility has been demonstrated.
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Polymyxin B can be considered in combination with at least one other agent for the treatment of CRAB infections.
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High-dose minocycline or high-dose tigecycline can be considered in combination with at least one other agent for the treatment of CRAB infections. The panel prefers minocycline because of the long-standing clinical experience with this agent and the availability of CLSI susceptibility interpretive criteria; however, tigecycline is also a reasonable option.
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Cefiderocol should be limited to the treatment of CRAB infections refractory to other antibiotics or in cases where intolerance or resistance to other agents precludes their use. When cefiderocol is used to treat CRAB infections, the panel suggests prescribing the agent as part of a combination regimen.
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High-dose, extended-infusion meropenem or imipenem-cilastatin are not suggested for the treatment of CRAB infections.
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Rifabutin or other rifamycins are not suggested for the treatment of CRAB infections.
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Nebulized antibiotics are not suggested for the treatment of respiratory infections caused by CRAB.
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Stenotrophomonas maltophilia
Any of two approaches are suggested for the treatment of S. maltophilia infections: (1) the use of two of the following agents: TMP-SMX, minocycline/tigecycline, cefiderocol, or levofloxacin or (2) the combination of ceftazidime-avibactam and aztreonam, when significant clinical instability is evident or intolerance to or inactivity of other agents is identified.
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TMP-SMX as a component of combination therapy, at least until clinical improvement is observed, is a preferred therapy for the treatment of S. maltophilia infections.
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High-dose minocycline (i.e., 200 milligrams IV/orally every 12 hours) as a component of combination therapy, at least until clinical improvement is observed, is a preferred therapy for the treatment of S. maltophilia infections. Because of the slightly more favorable in vitro data with minocycline, availability of CLSI breakpoints, oral formulation, and likely improved tolerability of minocycline relative to tigecycline, the panel favors minocycline over tigecycline, although tigecycline is also a reasonable treatment option for S. maltophilia infections.
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Cefiderocol as a component of combination therapy, at least until clinical improvement is observed, is a preferred therapy for the treatment of S. maltophilia infections.
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The combination of ceftazidime-avibactam and aztreonam is suggested for S. maltophilia infections when critical illness is evident or intolerance or inactivity of other agents is observed.
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Ceftazidime is not a suggested treatment option for S. maltophilia infections due to the presence of β-lactamase genes intrinsic to S. maltophilia that are expected to render ceftazidime inactive.
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Recommendation Grading
Overview
Title
Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections
Authoring Organization
Infectious Diseases Society of America
Publication Month/Year
June 7, 2023
Last Updated Month/Year
February 14, 2024
Document Type
Consensus
External Publication Status
Published
Country of Publication
US
Document Objectives
The overarching goal of this guidance document is to assist clinicians – including those with and without infectious diseases expertise – in selecting antibiotic therapy for infections caused by ESBL-E, CRE, and DTR-P. aeruginosa.
Inclusion Criteria
Male, Female, Adolescent, Adult, Child, Infant, Older adult
Health Care Settings
Ambulatory, Emergency care, Hospital, Long term care, Operating and recovery room
Intended Users
Epidemiology infection prevention, nurse, nurse practitioner, physician, physician assistant
Scope
Treatment
Diseases/Conditions (MeSH)
D011549 - Pseudomonas, D011552 - Pseudomonas Infections, D004754 - Enterobacter, D004756 - Enterobacteriaceae Infections, D006088 - Gram-Negative Aerobic Bacteria, D006090 - Gram-Negative Bacteria, D004351 - Drug Resistance
Keywords
Pseudomonas aeruginosa, Antibiotic Resistance, SSTI, gram-negative, AMR, Carbapenem-Resistant Enterobacterales, Extended-Spectrum β-lactamase Producing Enterobacterales