Editor's Note: As antimicrobial resistance (AMR) continues to be a growing global public health challenge, treating infections caused by resistant bacteria has become increasingly difficult. Recently, the Infectious Diseases Society of America (IDSA) released the "IDSA 2024 Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections," providing clinicians with valuable treatment recommendations. This document primarily addresses infections caused by extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-E), AmpC beta-lactamase-producing Enterobacterales (AmpC-E), carbapenem-resistant Enterobacterales (CRE), difficult-to-treat resistant Pseudomonas aeruginosa (DTR-PA), carbapenem-resistant Acinetobacter baumannii (CRAB), and Stenotrophomonas maltophilia, offering specific and comprehensive treatment advice. Infectious Disease Frontier has translated and summarized the relevant recommendations from the document for reference by our readers.

Note: This article may contain inaccuracies and is for reference only. Please follow national guidelines/expert consensus for specific clinical practices.

Part 1: General Management Recommendations

The treatment methods recommended in this guideline are based on the identification of the pathogen and the proven in vitro activity of the antimicrobial agents. When two antimicrobial agents have similar efficacy, factors to consider in drug selection include safety, cost, convenience, and local availability of the drug.

Definition of Complicated Urinary Tract Infection (cUTI)

In this document, cUTI refers to urinary tract infections associated with structural or functional abnormalities of the urogenital tract, or any urinary tract infection occurring in adolescent and adult males. Generally, the expert panel recommends using the same drugs and treatment duration for cUTI as for the treatment of pyelonephritis. For cUTI patients whose source of infection has been effectively controlled (e.g., Foley catheter removal) and who do not have persistent urinary retention or an indwelling catheter, the choice and duration of antibiotics are similar to those for uncomplicated cystitis. The treatment begins on the day the source of infection is controlled.

Empirical Therapy

Empirical therapy decisions are not within the scope of this guideline. However, in general, when developing an empirical treatment plan, consideration should be given to the most likely pathogens, the severity of the patient’s condition, the potential source of infection, and any specific patient factors (e.g., severe penicillin allergy, severe immunocompromise, chronic kidney disease). When formulating an empirical treatment plan for a patient, clinicians should also consider the following factors:

1. Microorganisms isolated in the past 12 months and their associated antimicrobial susceptibility test (AST) data.
2. Antimicrobial exposure in the past 3 months.
3. Local pathogen prevalence and their sensitivity or resistance distribution to various antimicrobials. Treatment decisions should be based on the type of pathogen and AST characteristics, combined with any detected significant beta-lactamase gene information, to further optimize the treatment plan. For all microorganisms, particularly difficult-to-treat Pseudomonas aeruginosa (DTR-PA), carbapenem-resistant Acinetobacter baumannii (CRAB), and Stenotrophomonas maltophilia, it is crucial to distinguish between bacterial colonization and infection. Unnecessary antimicrobial treatment not only exacerbates the development of resistance but may also cause unnecessary antimicrobial-related harm to the patient. Common empirical antimicrobial regimens are usually ineffective against CRAB and Stenotrophomonas maltophilia infections. When deciding whether to include these two bacteria in empirical antimicrobial therapy, it is important to thoroughly review the patient’s previous microbiological culture results, clinical presentation, host-specific risk factors, and the potential specific adverse events associated with antimicrobial agents, followed by a careful risk-benefit analysis.

Duration and Transition to Oral Therapy

This guideline does not provide specific recommendations on treatment duration. However, it advises clinicians not to vary the treatment duration for infections caused by resistant phenotypes from that of sensitive phenotypes. Upon obtaining AST results, it may be found that the empiric therapy used is ineffective against the pathogen, which could affect the duration of treatment. For uncomplicated cystitis, a mild infection, even if the empiric therapy used has no definitive efficacy against the pathogen, if the patient’s clinical symptoms have improved, it is generally unnecessary to repeat urine culture, change antimicrobial treatment, or extend the original treatment duration. For all other infections, if AST results suggest that a potentially inactive drug was used in the empiric regimen, it is recommended to switch to an active drug for a full course of treatment (starting from the time active drug therapy begins). Additionally, as with any bacterial infection, when determining the duration of AMR infection treatment, it is important to consider significant host factors related to immune status, source control capability, and overall response to treatment. Finally, where possible, transitioning to oral therapy (assuming initial intravenous treatment) should be considered, particularly when the following conditions are met:

1. Sensitivity to the corresponding oral drug has been demonstrated;
2. The patient is hemodynamically stable;
3. Appropriate source control measures have been implemented;
4. There are no issues with inadequate intestinal absorption.

Table 2. Breakpoints for Selected Gram-Negative Bacteria and Antimicrobial Combinations as Recommended by the Clinical and Laboratory Standards Institute (CLSI) in 2024 for the IDSA AMR Guidelines

·  For full details on the interpretation of antimicrobial susceptibility testing, please refer to: Clinical and Laboratory Standards Institute. 2024. M100: Performance Standards for Antimicrobial Susceptibility Testing. 34th ed. Wayne, PA. The CLSI M100 document is updated annually; the susceptibility standards will be updated in 2025.

·  Breakpoints apply only to urinary tract infections.

·  Cefepime is dose-dependent susceptible when the MIC is between 4-8 µg/mL.

·  Colistin or Polymyxin B has no susceptibility category; MIC ≤2 µg/mL is considered intermediate.

·  Applies only to urinary isolates of Escherichia coli.

·  Piperacillin-tazobactam is dose-dependent susceptible when the MIC is 16 µg/mL.

·  No CLSI breakpoint. The US FDA defines MIC ≤2 µg/mL as susceptible.

·  Neither CLSI nor the US FDA has established breakpoints.

Part 2

Extended-Spectrum β-Lactamase-Producing Enterobacterales (ESBL-E)

Question 1.1: What is the preferred antimicrobial therapy for treating uncomplicated cystitis caused by ESBL-E? Recommendation: The preferred antimicrobials are nitrofurantoin and SMZ-TMP. Ciprofloxacin, levofloxacin, and carbapenems are alternative options but are not recommended if nitrofurantoin or SMZ-TMP are effective. Aminoglycosides (single dose) and oral fosfomycin (only for E. coli) can also be considered as alternatives.

Question 1.2: What is the preferred antimicrobial therapy for treating pyelonephritis or complicated UTIs caused by ESBL-E? Recommendation: SMZ-TMP, ciprofloxacin, or levofloxacin are the preferred options. If SMZ-TMP or fluoroquinolones cannot be used due to resistance or toxicity, ertapenem, meropenem, and imipenem-cilastatin are preferred. Aminoglycosides are an alternative choice.

Question 1.3: What is the preferred antimicrobial therapy for treating non-UTI infections caused by ESBL-E? Recommendation: Meropenem, imipenem-cilastatin, or ertapenem are the preferred options. For severe cases and/or patients with hypoalbuminemia, meropenem or imipenem-cilastatin are the preferred carbapenems. After an appropriate clinical response is observed, consider transitioning to oral SMZ-TMP, ciprofloxacin, or levofloxacin if susceptibility is indicated.

Question 1.4: Does piperacillin-tazobactam play a role in treating infections caused by ESBL-E? Recommendation: For uncomplicated cystitis caused by ESBL-E, if clinical improvement is observed with initial empirical therapy using piperacillin-tazobactam, no change or extension of antimicrobial therapy is needed. For pyelonephritis or complicated UTIs caused by ESBL-E, the expert panel recommends using SMZ-TMP, ciprofloxacin, levofloxacin, or carbapenems over piperacillin-tazobactam due to the potentially lower risk of clinical failure. Piperacillin-tazobactam is not recommended for non-UTI infections caused by ESBL-E, even if the isolate is susceptible.

Question 1.5: Does cefepime play a role in treating infections caused by ESBL-E? Recommendation: For uncomplicated cystitis caused by ESBL-E, if clinical improvement is observed with initial empirical therapy using cefepime, no change or extension of antimicrobial therapy is needed. The expert panel advises against using cefepime to treat pyelonephritis or complicated UTIs caused by ESBL-E. Cefepime is also not recommended for non-UTI infections caused by ESBL-E, even if the isolate is susceptible.

Question 1.6: Does the cephamycin class play a role in treating infections caused by ESBL-E? Recommendation: The cephamycin class (e.g., cefoxitin, cefotetan) is not recommended for treating infections caused by ESBL-E until more clinical outcome data and optimal dosing information are available.

Question 1.7: What is the role of new β-lactamase inhibitor combinations and cefiderocol in treating infections caused by ESBL-E? Recommendation: The expert panel recommends prioritizing the use of ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, cefolozane-tazobactam, and cefiderocol for treating infections caused by carbapenem-resistant organisms.

Part 3

AmpC β-Lactamase-Producing Enterobacterales (AmpC-E)

Question 2.1: Which common Enterobacterales species should be considered at moderate risk of clinically significant inducible AmpC gene production? Recommendation: Enterobacter cloacae complex, Klebsiella aerogenes, and Citrobacter freundii have a moderate risk of producing clinically significant inducible AmpC enzymes.

Question 2.2: What factors should be considered when selecting antimicrobials for infections caused by Enterobacterales at moderate risk of inducible AmpC enzyme production? Recommendation: Several β-lactam antimicrobials have a moderate risk of inducing AmpC gene expression. Both the ability to induce AmpC and the relative stability of the drug against AmpC hydrolysis should guide antimicrobial selection.

Question 2.3: What is the role of cefepime in treating infections caused by Enterobacterales at moderate risk of inducible AmpC enzyme production? Recommendation: Cefepime is recommended for treating infections caused by Enterobacterales at moderate risk of AmpC enzyme production (e.g., Enterobacter cloacae complex, Klebsiella aerogenes, and Citrobacter freundii).

Question 2.4: What is the role of ceftriaxone in treating infections caused by Enterobacterales at moderate risk of inducible AmpC enzyme production? Recommendation: Ceftriaxone (or cefotaxime or ceftazidime) is not recommended for treating invasive infections caused by Enterobacterales at moderate risk of AmpC enzyme production (e.g., Enterobacter cloacae complex, Klebsiella aerogenes, and Citrobacter freundii). Ceftriaxone can be used to treat uncomplicated cystitis caused by these organisms if the pathogen is susceptible.

Question 2.5: What is the role of piperacillin-tazobactam in treating infections caused by Enterobacterales at moderate risk of inducible AmpC enzyme production? Recommendation: Piperacillin-tazobactam is not recommended for treating invasive infections caused by Enterobacterales at moderate risk of AmpC enzyme production.

Question 2.6: What is the role of new β-lactamase inhibitor combinations and cefiderocol in treating infections caused by Enterobacterales at moderate risk of inducible AmpC enzyme production? Recommendation: The expert panel recommends prioritizing the use of ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, and cefiderocol for treating carbapenem-resistant infections. The panel does not recommend cefolozane-tazobactam as a treatment option for AmpC-E infections.

Question 2.7: What is the role of non-β-lactam antimicrobials in treating infections caused by Enterobacterales at moderate risk of inducible AmpC enzyme production? Recommendation: For uncomplicated cystitis caused by AmpC-E, nitrofurantoin and SMZ-TMP are the preferred treatments. Ciprofloxacin, levofloxacin, or aminoglycosides (single dose) are alternative options for treating uncomplicated cystitis caused by AmpC-E. For pyelonephritis or complicated UTIs caused by AmpC-E, SMZ-TMP, ciprofloxacin, or levofloxacin are the preferred treatments.

Part 4

Carbapenem-Resistant Enterobacterales (CRE)

Question 3.1: What is the preferred antimicrobial therapy for treating uncomplicated cystitis caused by CRE? Recommendation: The preferred antimicrobials are nitrofurantoin, SMZ-TMP, ciprofloxacin, or levofloxacin, although the likelihood of susceptibility to these drugs may be low. Aminoglycosides (single dose), oral fosfomycin (only for E. coli), colistin, ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, or cefiderocol are alternative treatment options.

Question 3.2: What is the preferred antimicrobial therapy for treating pyelonephritis or complicated UTIs caused by CRE? Recommendation: If susceptible, SMZ-TMP, ciprofloxacin, or levofloxacin are the preferred options. Ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, and cefiderocol are also preferred treatment options. Aminoglycosides are an alternative choice.

Question 3.3: What is the preferred antimicrobial therapy for treating non-UTI infections caused by non-carbapenemase-producing CRE? Recommendation: If the isolate is susceptible to meropenem and imipenem (MIC ≤1 µg/mL) but not to ertapenem (MIC ≥1 µg/mL), prolonged infusion of meropenem (or imipenem-cilastatin) is recommended. If the isolate is not susceptible to any carbapenems, ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-cilastatin-relebactam are the preferred options.

Question 3.4: What is the preferred antimicrobial therapy for treating non-UTI infections caused by KPC-producing CRE? Recommendation: Meropenem-vaborbactam, ceftazidime-avibactam, and imipenem-cilastatin-relebactam are the preferred options. Cefiderocol is an alternative option.

Question 3.5: What is the preferred antimicrobial therapy for treating non-UTI infections caused by NDM- or other MBL-producing CRE? Recommendation: Ceftazidime-avibactam combined with aztreonam, or cefiderocol monotherapy, are the preferred options.

Question 3.6: What is the preferred antimicrobial therapy for treating non-UTI infections caused by OXA-48-like CRE? Recommendation: Ceftazidime-avibactam is the preferred option. Cefiderocol is an alternative treatment option.

Question 3.7: How likely is it for CRE to develop resistance to new β-lactam antibiotics? Recommendation: The emergence of resistance is a concern for all β-lactam antibiotics used to treat CRE infections. Existing data suggest that ceftazidime-avibactam may have the highest incidence of resistance.

Question 3.8: What is the role of tetracycline derivatives in treating CRE infections? Recommendation: Although β-lactam antibiotics remain the preferred drugs for treating CRE infections, tigecycline and eravacycline can be considered as alternative options when β-lactams are ineffective or intolerable. Tetracycline derivatives are not recommended for treating CRE UTIs or bloodstream infections.

Question 3.9: What is the role of polymyxins in treating CRE infections? Recommendation: Polymyxin B and colistin are not recommended for treating CRE infections. Colistin is an alternative drug for treating uncomplicated cystitis caused by CRE.

Question 3.10: What is the role of combination therapy in treating CRE infections? Recommendation: Combination therapy (i.e., using a β-lactam antibiotic alongside an aminoglycoside, fluoroquinolone, tetracycline, or polymyxin) is not recommended for treating CRE infections.

Part 5

Difficult-to-Treat Resistant Pseudomonas aeruginosa (DTR-PA)

Question 4.1: What is the preferred antimicrobial therapy for treating infections caused by multidrug-resistant (MDR) Pseudomonas aeruginosa? Recommendation: If the P. aeruginosa isolate is susceptible to traditional non-carbapenem β-lactam drugs (e.g., piperacillin-tazobactam, ceftazidime, cefepime, aztreonam) and carbapenems, the former are preferred. For P. aeruginosa infections resistant to carbapenems but susceptible to traditional β-lactam drugs, high-dose prolonged infusion of traditional β-lactams is recommended. For critically ill patients or those with poor source control, new β-lactam drugs (e.g., cefolozane-tazobactam, ceftazidime-avibactam, imipenem-cilastatin-relebactam) that are active against P. aeruginosa are also reasonable options.

Question 4.2: Is there a difference in the activity of available β-lactam antibiotics against DTR-PA? Recommendation: There is variability in the susceptibility rates of DTR-PA isolates to new β-lactam antibiotics, partly due to regional differences in resistance mechanisms.

Question 4.3: What is the preferred antimicrobial therapy for treating uncomplicated cystitis caused by DTR-PA? Recommendation: Cefolozane-tazobactam, ceftazidime-avibactam, imipenem-cilastatin-relebactam, and cefiderocol are the preferred options. Tobramycin or amikacin (single dose) are alternative treatment options.

Question 4.4: What is the preferred antimicrobial therapy for treating pyelonephritis or complicated UTIs caused by DTR-PA? Recommendation: Cefolozane-tazobactam, ceftazidime-avibactam, imipenem-cilastatin-relebactam, and cefiderocol are the preferred options. Once-daily tobramycin or amikacin are alternative drugs.

Question 4.5: What is the preferred antimicrobial therapy for treating non-UTI infections caused by DTR-PA? Recommendation: Cefolozane-tazobactam, ceftazidime-avibactam, and imipenem-cilastatin-relebactam are the preferred options. Cefiderocol is an alternative treatment option.

Question 4.6: What is the preferred antimicrobial therapy for treating infections caused by MBL-producing DTR-PA? Recommendation: Cefiderocol is the preferred option.

Question 4.7: How likely is it for DTR-PA to develop resistance to new β-lactam antibiotics? Recommendation: The emergence of resistance is a concern for all β-lactam antibiotics used to treat DTR-PA infections. Existing data suggest that cefolozane-tazobactam and ceftazidime-avibactam may have the highest incidence of resistance, although data on imipenem-cilastatin-relebactam and cefiderocol are limited.

Question 4.8: What is the role of combination therapy in treating DTR-PA infections? Recommendation: If DTR-PA is confirmed to be susceptible to cefolozane-tazobactam, ceftazidime-avibactam, imipenem-cilastatin-relebactam, or cefiderocol, combination therapy is not recommended.

Question 4.9: What is the role of inhaled antibiotics in treating DTR-PA respiratory infections? Recommendation: The expert panel does not recommend using inhaled antibiotics for treating DTR-PA respiratory infections.

Part 6

Carbapenem-Resistant Acinetobacter baumannii (CRAB)

Question 5.1: What is the general approach to treating CRAB infections? Recommendation: A sulbactam-containing regimen is recommended. The preferred regimen is sulbactam-durlobactam combined with a carbapenem (e.g., imipenem-cilastatin or meropenem). If sulbactam-durlobactam is unavailable, high-dose ampicillin-sulbactam (total daily sulbactam dose of 9 g) combined with at least one other drug (e.g., polymyxin B, minocycline > tigecycline, or cefiderocol) can be considered as an alternative.

Question 5.2: What is the role of sulbactam-durlobactam in treating CRAB infections? Recommendation: Sulbactam-durlobactam is the preferred drug for treating CRAB infections, recommended in combination with imipenem-cilastatin or meropenem.

Question 5.3: What is the role of ampicillin-sulbactam in treating CRAB infections? Recommendation: High-dose ampicillin-sulbactam is recommended as part of combination therapy and as an alternative for treating CRAB infections. This approach is recommended only when sulbactam-durlobactam is unavailable.

Question 5.4: What is the role of combination therapy in treating CRAB infections? Recommendation: Given the limited clinical data supporting monotherapy, combination therapy with at least two active drugs is recommended whenever possible, at least until clinical improvement is observed.

Question 5.5: What is the role of polymyxins in treating CRAB infections? Recommendation: Polymyxin B can be considered as part of combination therapy for treating CRAB infections.

Question 5.6: What is the role of tetracycline derivatives in treating CRAB infections? Recommendation: High-dose minocycline or high-dose tigecycline can be considered as part of combination therapy for treating CRAB infections. The expert panel prefers minocycline over tigecycline due to its longer clinical experience and available CLSI breakpoints.

Question 5.7: What is the role of cefiderocol in treating CRAB infections? Recommendation: Cefiderocol should be reserved for treating CRAB infections that are refractory to other antibiotics or for cases where other drugs are not tolerated or have developed resistance. The expert panel recommends its use as part of combination therapy.

Question 5.8: What is the role of prolonged infusion meropenem or imipenem-cilastatin in treating CRAB infections? Recommendation: Meropenem or imipenem-cilastatin are not recommended for treating CRAB infections except when combined with sulbactam-durlobactam.

Question 5.9: What is the role of rifamycins in treating CRAB infections? Recommendation: Rifampin or other rifamycins are not recommended for treating CRAB infections.

Question 5.10: What is the role of inhaled antibiotics in treating CRAB respiratory infections? Recommendation: Inhaled antibiotics are not recommended for treating CRAB respiratory infections.

Part 7

Stenotrophomonas maltophilia

Question 6.1: What is the general approach to treating S. maltophilia infections? Recommendation: The preferred options are either of the following: (1) use two of the following drugs: cefiderocol, minocycline, SMZ-TMP, or levofloxacin; (2) ceftazidime-avibactam combined with aztreonam.

Question 6.2: What is the role of cefiderocol in treating S. maltophilia infections? Recommendation: Cefiderocol, as part of combination therapy, is the preferred drug for treating S. maltophilia infections, at least until clinical improvement is observed.

Question 6.3: What is the role of ceftazidime-avibactam and aztreonam in treating S. maltophilia infections? Recommendation: Ceftazidime-avibactam and aztreonam is the preferred combination for treating S. maltophilia infections.

Question 6.4: What is the role of tetracycline derivatives in treating S. maltophilia infections? Recommendation: High-dose minocycline, as part of combination therapy, is an option for treating S. maltophilia infections.

Question 6.5: What is the role of SMZ-TMP in treating S. maltophilia infections? Recommendation: SMZ-TMP, as part of combination therapy, is an option for treating S. maltophilia infections.

Question 6.6: What is the role of fluoroquinolones in treating S. maltophilia infections? Recommendation: Levofloxacin, as part of combination therapy, is an option for treating S. maltophilia infections.

Question 6.7: What is the role of ceftazidime in treating S. maltophilia infections? Recommendation: Due to the inherent β-lactamase genes of S. maltophilia that can inactivate ceftazidime, ceftazidime is not recommended as a treatment option for S. maltophilia infections. As of 2024, CLSI no longer provides breakpoints for ceftazidime against S. maltophilia.